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Sample records for antibody rituximab radioimmunotherapy

  1. Standard Operating Procedure for Prospective Individualised Dosimetry for ([131])I-rituximab Radioimmunotherapy of Non-Hodgkin's Lymphoma.

    PubMed

    Calais, Phillipe J; Turner, J Harvey

    2012-09-01

    Radioimmunotherapy (RIT) is an attractive therapy for non-Hodgkin's lymphoma (NHL) as it allows targeted tumor irradiation which provides a cytotoxic effect significantly greater than that of the immune-mediated effects of a non-radioactive, or 'cold', antibody alone. Anti-CD20 antibodies such as rituximab are ideal for RIT, as not only is it easily iodinated, but the CD20 antigen is found on more than 95% of B-cell NHL. A standard operating procedure (SOP) has been formulated for personalized prospective dosimetry for safe, effective outpatient (131)I-rituximab RIT of NHL. Over five years, experience of treatment of outpatients with (131)I-rituximab was analyzed with respect to critical organ radiation dose in patients and radiation exposure of their carers. This radiation safety methodology has been refined; and offers the potential for safe, practical application to outpatient (131)I-rituximab RIT of lymphoma in general and in developing countries in particular. Given endorsement and sanction of this SOP by local regulatory authorities the personalized dosimetry paradigm will facilitate incorporation of RIT into the routine clinical practice of therapeutic nuclear oncology worldwide. PMID:23372448

  2. Use of second antibody in radioimmunotherapy

    SciTech Connect

    Begent, R.H.; Bagshawe, K.D.; Pedley, R.B.; Searle, F.; Ledermann, J.A.; Green, A.J.; Keep, P.A.; Chester, K.A.; Glaser, M.G.; Dale, R.G.

    1987-01-01

    In this study, a second antibody was directed against the first antitumor antibody to accelerate clearance of the /sup 131/I-labeled first antibody and improve tumor to normal tissue ratios of radioactivity. The value of this method in improving the therapeutic index of radioimmunotherapy with /sup 131/I-antibody to CEA has been investigated in nude mice bearing xenografts of human colon carcinoma and in 5 patients with colorectal cancer. The xenografts did not become saturated with anti-CEA as the administered dose was increased to therapeutic levels. At these high dose levels, the second antibody increased tumor to blood ratios to a maximum of 155:1, 48 times the level in controls that did not receive the second antibody. In 5 patients given 50 mCi of anti-CEA, there was no significant toxicity with the second antibody; clearance of radioactivity was accelerated; and tumor imaging was enhanced. The second antibody appears to have the potential to improve the therapeutic index of radioimmunotherapy.

  3. Standard Operating Procedure for In-house Preparation of (131)I-rituximab for Radioimmunotherapy of Non-Hodgkin's Lymphoma.

    PubMed

    Pickford, Matthew D; Turner, J Harvey

    2012-09-01

    A Standard Operating Procedure (SOP) has been formulated for in-house preparation, quality control, dispensing and administration of (131)I-rituximab appropriate for the safe, effective, radioimmunotherapy of non-Hodgkin lymphoma. A decade of experience of semi-automated radioiodination of rituximab in our hospital radiopharmaceutical laboratory was analysed. The methodology was then refined for safe, practical, affordable application to radioimmunotherapy of lymphoma in departments of nuclear medicine in developing countries. This SOP has the potential to be incorporated into good laboratory practice conditions appropriate for local regulatory agency requirements. PMID:23372447

  4. Standard Operating Procedure for In-house Preparation of 131I-rituximab for Radioimmunotherapy of Non-Hodgkin's Lymphoma

    PubMed Central

    Pickford, Matthew D.; Turner, J. Harvey

    2012-01-01

    A Standard Operating Procedure (SOP) has been formulated for in-house preparation, quality control, dispensing and administration of 131I-rituximab appropriate for the safe, effective, radioimmunotherapy of non-Hodgkin lymphoma. A decade of experience of semi-automated radioiodination of rituximab in our hospital radiopharmaceutical laboratory was analysed. The methodology was then refined for safe, practical, affordable application to radioimmunotherapy of lymphoma in departments of nuclear medicine in developing countries. This SOP has the potential to be incorporated into good laboratory practice conditions appropriate for local regulatory agency requirements. PMID:23372447

  5. An approach for conjugation of 177Lu- DOTA-SCN- Rituximab (BioSim) & its evaluation for radioimmunotherapy of relapsed & refractory B-cell non Hodgkins lymphoma patients

    PubMed Central

    Thakral, Parul; Singla, Suhas; Yadav, Madhav Prasad; Vasisht, Atul; Sharma, Atul; Gupta, Santosh Kumar; Bal, C.S.; Snehlata; Malhotra, Arun

    2014-01-01

    Background & objectives: The prerequisite of radioimmunotherapy is stable binding of a radionuclide to monoclonal antibodies, which are specific to the tumour-associated antigen. Most B-cell lymphomas express CD20 antigen on the surface of the tumour cells, making it a suitable target for therapeutic radioactive monoclonal antibodies. In the present study, the immunoconjugate of biosimilar Rituximab (Reditux™) and macrocyclic chelator, p-SCN-Bz-DOTA, was prepared and radiolabelled with Lutetium-177 followed by quality control procedures. Methods: Rituximab(BioSim) was desalted with sodium bicarbonate (0.1M, pH 9.0) and incubated with DOTA-SCN (1:50). The effectiveness of the conjugation was evaluated by determining the number of chelators per antibody molecule. This conjugate was radiolabelled with Lutetium-177 and purified using PD10 column. The quality control parameters like pH, clarity, radiochemical purity, in vitro stability and sterility were studied. Immunoreactivity of 177Lu-DOTA-Rituximab (BioSim) was assessed using RAMOS cells. The radioimmunoconjugate (RIC) after stringent quality assurance was injected in three patients and the biodistribution profile was analysed. Results: An average of 4.25 ± 1.04 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single molecule of Rituximab (BioSim). The radiochemical purity of the labelled antibody was > 95 per cent with preserved affinity for CD20 antigen. The final preparation was stable up to about 120 h when tested under different conditions. A favourable biodistribution profile was observed with liver showing the maximum uptake of the RIC. Interpretation & conclusions: A favourable radiochemical purity, stability and biodistribution of the radiolabelled immunoconjugate indicate that clinical trials for evaluation of toxicity and efficacy of 177Lu-DOTA-antiCD20 antibody-Rituximab (BioSim) in patients of relapsed and refractory non Hodgkin's lymphoma can be considered. PMID:24927340

  6. Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients.

    PubMed

    Leahy, Michael F; Turner, J Harvey

    2011-01-01

    Radioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) has achieved objective response rates in clinical trials comparable with standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, but is relatively underused in routine practice. In this article, we report our clinical experience in 142 consecutive patients who received iodine-131 rituximab radioimmunotherapy for low-grade, predominantly follicular, relapsed NHL. Objective response rates of 67%, with complete response (CR) in 50% and median overall survival of 32 months, matched the response rates in a phase 2 clinical trial of (131)I-rituximab radioimmunotherapy and compares favorably with those reported for (131)I-tositumomab or (90)Y-ibritumomab tiuxetan. Progression-free survival was 18 months overall and 32 months in CR or CR-unconfirmed patients. Our patients comprised 107 (75%) follicular lymphoma, 21 (15%) small lymphocytic lymphoma, 6 (4%) mucosa-associated lymphoid tissue/marginal zone lymphoma, and 8 (6%) mantle-cell lymphoma, with median follow-up of 32 months and 8-year overall survival of 48%. Toxicity was limited to hematologic grade 4 neutropenia, occurring in 10% and thrombocytopenia in 6%. There were no episodes of bleeding or infection requiring hospital admission. Radioimmunotherapy with (131)I-rituximab in routine clinical outpatient practice provides cost-effective, safe treatment of relapsed/refractory indolent NHL, with half of patients achieving durable, complete remission with potential for repeat radioimmunotherapy on relapse. PMID:20864582

  7. A phase 2 study of inotuzumab ozogamicin in patients with indolent B-cell non-Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy.

    PubMed

    Goy, Andre; Forero, Andres; Wagner-Johnston, Nina; Christopher Ehmann, W; Tsai, Michaela; Hatake, Kiyohiko; Ananthakrishnan, Revathi; Volkert, Angela; Vandendries, Erik; Ogura, Michinori

    2016-08-01

    This phase 2 study evaluated the efficacy and safety of inotuzumab ozogamicin (InO) in patients with indolent B-cell non-Hodgkin lymphoma (NHL) refractory to rituximab alone, rituximab plus chemotherapy or anti-CD20 radioimmunotherapy. Patients received InO 1·8 mg/m(2) intravenously on a 28-d cycle for a planned 4-8 cycles. The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a complete response (CR). The primary endpoint was overall response. Eighty-one patients were enrolled, among whom 48 (59%) received ≥3 InO cycles and 13 (16%) completed the treatment phase. The overall response rate was 67% (CR, 31%). Median (95% confidence interval) progression-free survival was 12·7 (8·9-26·9) months; median overall survival was not reached. Haematological adverse events (AEs) were common, particularly thrombocytopenia (74%) and neutropenia (56%). These were also the most common AEs leading to treatment discontinuation (37% and 11%, respectively); 58% of patients reported AEs leading to treatment discontinuation. InO demonstrated robust activity in these heavily pretreated patients, although treatment duration was limited by haematological toxicities. Additional studies may determine dosing regimens that allow for reduced toxicity. PMID:27101934

  8. Microdosimetric model of astatine-211 labeled antibodies for radioimmunotherapy

    SciTech Connect

    Humm, J.L.

    1987-11-01

    Astatine-211 is an alpha-emitter with a short half-life (7.2 hr). This paper discusses the potential of /sup 211/At targeted by antibodies for tumor therapy and the possible advantage of /sup 211/At over beta- and gamma-emitting radionuclides such as /sup 131/I currently employed in the field of radioimmunotherapy. Since the longest range alpha-particle from /sup 211/At is only 67 microns and the rate of energy loss is high (track averaged linear energy transfer LT approximately 120 keV/micron), a disintegration of /sup 211/At produces a large and extremely localized deposition of energy. A Monte-Carlo model has been developed for studying the stochastic fluctuation of alpha-particle hits and energy deposition in cell nuclei in an attempt to determine the efficacy of /sup 211/At-labeled antibodies for tumor cell inactivation. Calculations have been performed for 2 extreme conditions: (a) the case of /sup 211/At retained in the capillary, and (b) for a homogeneous distribution of /sup 211/At-labeled antibody in the tumor. The results of these two calculations represent the boundary conditions between which any real solution must lie. Finally, developments to the model to include antibody transport across the capillary membrane and through the tumor tissue are discussed.

  9. Radioimmunotherapy Combined with Maintenance Anti-CD20 Antibody May Trigger Long-Term Protective T Cell Immunity in Follicular Lymphoma Patients

    PubMed Central

    Buchegger, Franz; Larson, Steven M.; Mach, Jean-Pierre; Dietrich, Pierre-Yves; Cairoli, Anne; Prior, John O.; Romero, Pedro; Speiser, Daniel E.

    2013-01-01

    Growing evidence suggests that the patient's immune response may play a major role in the long-term efficacy of antibody therapies of follicular lymphoma (FL). Particular long-lasting recurrence free survivals have been observed after first line, single agent rituximab or after radioimmunotherapy (RIT). Rituximab maintenance, furthermore, has a major efficacy in prolonging recurrence free survival after chemotherapy. On the other hand, RIT as a single step treatment showed a remarkable capacity to induce complete and partial remissions when applied in recurrence and as initial treatment of FL or given for consolidation. These clinical results strongly suggest that RIT combined with rituximab maintenance could stabilize the high percentages of patients with CR and PR induced by RIT. While the precise mechanisms of the long-term efficacy of these 2 treatments are not elucidated, different observations suggest that the patient's T cell immune response could be decisive. With this review, we discuss the potential role of the patient's immune system under rituximab and RIT and argue that the T cell immunity might be particularly promoted when combining the 2 antibody treatments in the early therapy of FL. PMID:24371449

  10. Rituximab

    PubMed Central

    Storz, Ulrich

    2014-01-01

    Because drug development is not a static process, a drug’s market authorisation may change over time. In many cases, the number of indications for which a drug is approved increases. Because this facet of drug development also comes at significant costs, a corresponding patent filing strategy is required to protect these investments. The strategy as applied to rituximab, which is approved for a variety of indications, is discussed in this review. PMID:24866199

  11. Anti-JC virus antibodies in rituximab-treated patients with neuromyelitis optica spectrum disorder.

    PubMed

    Kim, Su-Hyun; Hyun, Jae-Won; Jeong, In Hye; Joung, AeRan; Yeon, Joung-Lim; Dehmel, Thomas; Adams, Ortwin; Kieseier, Bernd C; Kim, Ho Jin

    2015-03-01

    Rituximab, a chimeric monoclonal anti-CD20 antibody, has been proposed to be effective for neuromyelitis optica spectrum disorder (NMOSD). A concern for developing progressive multifocal leukoencephalopathy (PML), which is caused by John Cunningham virus (JCV), has been suggested particularly in patients treated long term with rituximab. In this study, using a modified enzyme-linked immunosorbent assay with glutathione S-transferase-tagged VP1 as the antigen, we investigated the seroprevalence of anti-JCV antibodies among 78 Korean patients with NMOSD and the change in anti-JCV antibody serostatus following long-term rituximab treatment. The overall seroprevalence of anti-JCV antibodies was 69 % prior to rituximab administration. Over a mean of 4 years of repeated treatment with rituximab, no patient developed PML. Of 24 initially seronegative patients, none converted into seropositive, whereas six (11 %) of 54 initially seropositive patients converted into seronegative. Our results might support the safety of long-term rituximab treatment in patients with NMOSD with regard to the risk of developing PML. PMID:25559683

  12. Cancer radioimmunotherapy

    PubMed Central

    Sharkey, Robert M; Goldenberg, David M

    2011-01-01

    Targeting of radionuclides with antibodies, or radioimmunotherapy, has been an active field of research spanning nearly 50 years, evolving with advancing technologies in molecular biology and chemistry, and with many important preclinical and clinical studies illustrating the benefits, but also the challenges, which all forms of targeted therapies face. There are currently two radiolabeled antibodies approved for the treatment of non-Hodgkin lymphoma, but radioimmunotherapy of solid tumors remains a challenge. Novel antibody constructs, focusing on treatment of localized and minimal disease, and pretargeting are all promising new approaches that are currently under investigation. PMID:21395378

  13. Real Time Analysis of Binding between Rituximab (anti-CD20 antibody) and B Lymphoma Cells

    PubMed Central

    Tan, Liang; Lin, Peiling; Chisti, Mohammad M.; Rehman, Abdul; Zeng, Xiangqun

    2013-01-01

    CD20, expressed on greater than 90% of B-lymphocytic lymphomas, is an attractive target for antibody therapy. Rituximab is a chimeric murine/human-engineered monoclonal antibody and can selectively deplete CD20-expressing cells in peripheral blood and lymphoid tissues. The immobilization of B-lymphoblast-like Burkitt's lymphoma Raji cells on the quartz crystal microbalance (QCM) gold electrode surface using RGD tripeptide was electrochemically confirmed. The real-time processes of attachment of Raji cells on the gold electrode and the subsequent binding of Rituximab to the cells were studied using QCM biosensor. The interaction between Rituximab and Raji cells led to the increased resonant frequency shifts (Δf0) in the studied antibody concentration range from 5 to 250 µg mL−1 following the Langmuir adsorption model. From these observations, the apparent binding constant between a single-layer of Rituximab and Raji cells was calculated to be 1.6×106 M−1. Control experiments using other therapeutic antibodies (i.e., Trastuzumab and Bevacizumab) and different cells (i.e., T cells and endothelial cells) proved the specific interaction between Rituximab and B cells. The effects of Ca2+ and Mn2+ ions on the Rituximab-Raji cell interaction were also studied providing the enhanced QCM signals, in particular, further indicating that CD20 is a calcium ion channel that can transport these metal ions into the cells and accelerate the cell lysis induced by Rituximab. Thus the real time capability of QCM and its simplicity of operation are highly suitable for multipurpose studies on living cells including cell-immobilization, cytotoxicity of drugs, and the cell action mechanisms. PMID:23926879

  14. In Vitro Cytotoxicity of Low-Dose-Rate Radioimmunotherapy by the Alpha-Emitting Radioimmunoconjugate Thorium-227-DOTA-Rituximab

    SciTech Connect

    Dahle, Jostein; Krogh, Cecilie; Melhus, Katrine B.; Borrebaek, Jorgen; Larsen, Roy H.; Kvinnsland, Yngve

    2009-11-01

    Purpose: To determine whether the low-dose-rate alpha-particle-emitting radioimmunoconjugate {sup 227}Th-1,4,7,10-p-isothiocyanato-benzyl-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (DOTA)-rituximab can be used to inactivate lymphoma cells growing as single cells and small colonies. Methods and Materials: CD20-positive lymphoma cell lines were treated with {sup 227}Th-DOTA-rituximab for 1-5 weeks. To simulate the in vivo situation with continuous but decreasing supply of radioimmunoconjugates from the blood pool, the cells were not washed after incubation with {sup 227}Th-DOTA-rituximab, but half of the medium was replaced with fresh medium, and cell concentration and cell-bound activity were determined every other day after start of incubation. A microdosimetric model was established to estimate the average number of hits in the nucleus for different localizations of activity. Results: There was a specific targeted effect on cell growth of the {sup 227}Th-DOTA-rituximab treatment. Although the cells were not washed after incubation with {sup 227}Th-DOTA-rituximab, the average contribution of activity in the medium to the mean dose was only 6%, whereas the average contribution from activity on the cells' own surface was 78%. The mean dose rates after incubation with 800 Bq/mL {sup 227}Th-DOTA-rituximab varied from 0.01 to 0.03 cGy/min. The average delay in growing from 10{sup 5} to 10{sup 7} cells/mL was 15 days when the cells were treated with a mean absorbed radiation dose of 2 Gy alpha-particle radiation from {sup 227}Th-DOTA-rituximab, whereas it was 11 days when the cells were irradiated with 6 Gy of X-radiation. The relative biologic effect of the treatment was estimated to be 2.9-3.4. Conclusions: The low-dose-rate radioimmunoconjugate {sup 227}Th-DOTA-rituximab is suitable for inactivation of single lymphoma cells and small colonies of lymphoma cells.

  15. Radioimmunotherapy: A Specific Treatment Protocol for Cancer by Cytotoxic Radioisotopes Conjugated to Antibodies

    PubMed Central

    Kawashima, Hidekazu

    2014-01-01

    Radioimmunotherapy (RIT) represents a selective internal radiation therapy, that is, the use of radionuclides conjugated to tumor-directed monoclonal antibodies (including those fragments) or peptides. In a clinical field, two successful examples of this treatment protocol are currently extended by 90Y-ibritumomab tiuxetan (Zevalin) and 131I-tositumomab (Bexxar), both of which are anti-CD20 monoclonal antibodies coupled to cytotoxic radioisotopes and are approved for the treatment of non-Hodgkin lymphoma patients. In addition, some beneficial observations are obtained in preclinical studies targeting solid tumors. To date, in order to reduce the unnecessary exposure and to enhance the therapeutic efficacy, various biological, chemical, and treatment procedural improvements have been investigated in RIT. This review outlines the fundamentals of RIT and current knowledge of the preclinical/clinical trials for cancer treatment. PMID:25379535

  16. Long-term remission with rituximab in refractory leucine-rich glioma inactivated 1 antibody encephalitis.

    PubMed

    Brown, J William L; Martin, Peter J; Thorpe, John W; Michell, Andrew W; Coles, Alasdair J; Cox, Amanda L; Vincent, Angela; Zandi, Michael S

    2014-06-15

    Autoimmune encephalitis associated with antibodies to leucine-rich glioma inactivated 1 (LGI1) is recently described and there is a lack of detailed reports on the treatment of relapsing or refractory cases and long-term outcomes. Two case reports are presented. Both cases had faciobrachial dystonic seizures (FBDS) and received rituximab after relapsing or refractory disease. Both cases achieved sustained clinical remission of up to 15 and 56 months respectively. Rituximab use allowed withdrawal of corticosteroids and was well tolerated. Randomized clinical trials are needed in LGI1 encephalitis and other autoimmune encephalitides. PMID:24703099

  17. Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis

    PubMed Central

    2013-01-01

    Introduction The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA). Methods Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post- and pre-vaccination antibody levels and a positive antibody response (posAR) was AR ≥2. Results In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%. Conclusion In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment. Trial registration NCT

  18. Pretargeted radioimmunotherapy

    SciTech Connect

    Meredith, Ruby F.; Buchsbaum, Donald J. . E-mail: djb@uab.edu

    2006-10-01

    This brief review covers the concept of pretargeted radioimmunotherapy and summarize the results obtained in preclinical animal models and initial phase I clinical trials. Reagents studied have been a bifunctional antibody prepared by crosslinking Fab' fragments from two antibodies with different specificity, one binding the target antigen expressed on tumors and the other binding a radiolabeled peptide. The alternative system is a conjugate of streptavidin linked to the pretargeting agent and radiolabeled biotin. After reaching optimal tumor targeting of the pretargeting agent, a synthetic mono-biotin poly N-acetyl-galactosamine compound was used to clear unbound targeting agent from the circulation before the injection of radiolabeled biotin. Promising therapeutic responses were obtained in various tumor xenograft models in athymic nude mice. A phase I study of an anti-CD20/streptavidin pretargeting agent and 15 mCi/m{sup 2} {sup 9}Y-biotin produced objective responses with minimal toxicity among lymphoma patients, with an average tumor-to-whole-body radiation dose ratio of 49. Pretargeting radioimmunotherapy approaches have shown higher tumor-to-whole-body ratios than that usually obtained with one-step radioimmunotherapy.

  19. The anti-CD20 monoclonal antibody rituximab to treat acquired haemophilia A

    PubMed Central

    D’Arena, Giovanni; Grandone, Elvira; Di Minno, Matteo N.D.; Musto, Pellegrino; Di Minno, Giovanni

    2016-01-01

    Background Acquired haemophilia A (AHA) is a rare bleeding disorder caused by the development of specific autoantibodies against naturally occurring factor VIII (FVIII). Although about half of cases are idiopathic, AHA may be associated with several non-neoplastic conditions, autoimmune disorders, as well as haematological malignancies, such as chronic lymphocytic leukaemia and lymphoma. The long-term suppression of inhibitors is one of the mainstays of the treatment of AHA. Apart from standard immunosuppressive treatments, rituximab has been proven to be effective in AHA. Materials and methods The aim of this review is to provide a systematic description of data available in the literature on this topic. To do so, we performed a search using the indexed online database Medline/PubMed, without temporal limits, matching the words “rituximab” and “acquired h(a)emophilia”. Furthermore, additional published studies were identified in the reference list of the publications found in PubMed. Results The review of the literature confirms that rituximab may be a safe and useful treatment for AHA. Discussion Although rituximab is not a standard therapy for AHA, it may be useful in resistant cases. However, the definitive place of this monoclonal antibody in the therapeutic strategy for AHA (first or second-line, alone or in combination with other drugs) remains to be determined more precisely and warrants further investigation. PMID:26509821

  20. Preparation & in vitro evaluation of 90Y-DOTA-rituximab

    PubMed Central

    Kameswaran, Mythili; Pandey, Usha; Dash, Ashutosh; Samuel, Grace; Venkatesh, Meera

    2016-01-01

    Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin's lymphoma (NHL). Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA) to rituximab, its radiolabelling with 90Y and in vitro and in vivo evaluation to determine its potential as a radioimmunotherapeutic agent. Methods: Rituximab was conjugated with p-SCN-Bn-DOTA at 1:1 antibody: DOTA molar ratio. The number of DOTA molecules linked to one molecule of rituximab was determined by radioassay and spectroscopic assay. Radiolabelling of rituximab with 90Y was carried out and its in vitro stability was evaluated. In vitro cell binding studies were carried out in Raji cells expressing CD20 antigen. Biodistribution studies were carried out in normal Swiss mice. Results: Using both radioassay and spectroscopic method, it was determined that about five molecules of DOTA were linked to rituximab. Radiolabelling of the rituximab conjugate with 90Y and subsequent purification on PD-10 column gave a product with radiochemical purity (RCP) > 98 per cent which was retained at > 90 per cent up to 72 h when stored at 37°C. In vitro cell binding experiments of 90Y-DOTA-rituximab with Raji cells exhibited specific binding of 20.7 ± 0.1 per cent with 90Y-DOTA-rituximab which reduced to 15.5 ± 0.2 per cent when incubated with cold rituximab. The equilibrium constant Kd for 90Y-DOTA-Rituximab was determined to be 3.38 nM. Radiolabelled antibody showed clearance via hepatobiliary and renal routes and activity in tibia was found to be quite low indicating in vivo stability of 90Y-DOTA-rituximab. Interpretation & conclusions: p-SCN-Bn-DOTA was conjugated with rituximab and radiolabelling with 90Y was carried out. In vitro studies carried

  1. Low-Dose Rituximab Therapy for Antibody-Mediated Rejection in a Highly Sensitized Heart-Transplant Recipient

    PubMed Central

    Aggarwal, Ashim; Pyle, Joseph; Hamilton, John; Bhat, Geetha

    2012-01-01

    Antibody-mediated rejection is the B-cell–mediated production of immunoglobulin G antibody against the transplanted heart. The currently available therapies for antibody-mediated rejection have had marginal success, and chronic manifestations of rejection can result in an increased risk of graft vasculopathy and perhaps require repeat transplantation. Rituximab, a monoclonal antibody directed against the CD20 receptor of B-lymphocytes and approved as therapy for lymphoma, can be used in heart-transplant patients for the management of antibody-mediated rejection. We present the case of a 52-year-old woman with high allosensitization (pre-transplantation panel reactive antibody level, 72%) who underwent successful orthotopic heart transplantation. Postoperatively, her acute antibody-mediated rejection with concomitant cellular rejection was successfully treated with low-dose rituximab. The patient died 5 months later because of multiple other medical problems. The present case suggests a role for low-dose rituximab as therapy for antibody-mediated rejection in heart-transplant patients. PMID:23304051

  2. Cholestatic Liver Disease after Rituximab and Adalimumab and the Possible Role of Cross-Reacting Antibodies to Fab 2 Fragments

    PubMed Central

    Koetter, Ina; Schwab, Matthias; Fritz, Peter; Kimmel, Martin; Alscher, M. Dominik; Braun, Niko

    2013-01-01

    Background Millions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases. We investigated sera from six patients who received immune globulin, from one patient with refractory anti-neutrophil-cytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis (GPA) who developed two episodes of acute cholestatic liver disease, one after treatment with rituximab and a second after adalimumab and a healthy control group. Methods Three sera from the patient and six sera from patients who received immune globulin were analyzed for antibodies to rituximab and adalimumab by ELISA. Additionally, sera from the patients and from nine healthy blood donors were coated with the Fab fragment of an unrelated humanized monoclonal antibody, with human Fc proteins as well as a mouse IgG globulin. Results Viral serology for hepatitis A, B, C and autoantibodies specific for autoimmune liver disorders were negative. In all three sera from the patient antibodies to rituximab could be detected, but also antibodies to adalimumab were present even at time points when the patient had not yet received adalimumab, indicating cross reactivity between both substances. Testing against an unrelated human Fab fragment revealed positive results, indicating that the patient had antibodies against human Fab fragments in general. The Fc proteins were negative, and patients’ sera did also not react with mouse IgG globulins. Remarkably, 2 out of 5 patients which were treated with immune globulin had antibodies against human Fab fragments in general whereas in none of the samples from healthy controls antibodies to Fab fragment could be detected. Conclusion This is the first study demonstrating cholestatic liver disease induced by two different Tmabs. Cross - reacting antibodies to Fab2 fragments in general are probably involved. Further studies must show if these Fab2 antibodies in general are related with drug-induced side effects and accelerated drug

  3. Radioimmunotherapy of malignancies

    SciTech Connect

    Reilly, R.M. )

    1991-05-01

    The critical issues in radioimmunotherapy are highlighted, and novel ways of improving the therapeutic indexes of radioimmunotherapeutic agents are outlined. The use of radioactively labeled monoclonal antibodies to treat malignant tumors has been investigated in animals and humans. Radionuclides suitable for labeling antibodies for such use include iodine 125, iodine 131, yttrium 90, rhenium 188, and copper 67. Radiobiological factors to be considered in radioimmunotherapy include the size and density of the tumor and the ability of a radiolabeled antibody to penetrate the tumor nodule. The dose of radiation required to destroy a tumor varies; however, the whole-body dose must not exceed 200 rads to avoid irreversible toxicity to the bone marrow. Despite the theoretical inadequacy of radiation doses to tumors indicated by conventional dosimetry, responses have been observed in animals and humans. More reliable and accurate dosimetric methods are under development. The induction of human antimouse antibodies can alter the pharmacokinetics of radiolabeled antibodies. Improving the therapeutic index of radioimmunotherapeutic agents may be achieved through regional therapy, administering a secondary antibody to improve clearance, combining radioimmunotherapy with external-beam irradiation, using an avidin-biotin conjugate system to deliver the radiolabeled antibodies, and addressing the problem of tumor antigen heterogeneity. Researchers are working to reduce or eliminate the clinical problems associated with radioimmunotherapy. Hematologic malignancies, such as lymphomas, are more likely than solid tumors to respond satisfactorily. 110 refs.

  4. Enhanced tumor retention of radioiodinated anti-epidermal growth factor receptor antibody using novel bifunctional iodination linker for radioimmunotherapy.

    PubMed

    Kim, Eun Jung; Kim, Byoung Soo; Choi, Dan Bee; Chi, Sung-Gil; Choi, Tae Hyun

    2016-06-01

    Radioimmunotherapy (RIT) uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target tumor cells. Radioiodine is most commonly employed to prepare radiolabeled proteins (antibodies, peptides) for in vitro and in vivo applications. A major shortcoming of radioiodinated proteins prepared by direct labeling methods is their deiodination in vivo. For the preparation of more stable radioiodinated antibodies, we developed a new linker (N-(4-isothiocyanatobenzyl)-2-(3-(tributylstannyl)phenyl) acetamide (IBPA). This study evaluated the usefulness of IBPA as a linker for the stable radioiodinated internalizing antibody, cetuximab. Directly labeled cetuximab ([125I]-cetuximab) was prepared by the chloramine T method. To prepare indirectly labeled cetuximab using IBPA ([125I]-IBPA-cetuximab), IBPA was radioiodinated using chloramine-T to give N-(4-isothiocyanatobenzyl)-2-(3-[125I]phenyl)acetamide ([125I]‑IBPA), which was purified by high performance liquid chromatography. [125I]-IBPA was then conjugated to cetuximab. In vitro target binding and internalizing assays were performed in PC9, LS174T, and FaDu cell lines. In vivo planar images were obtained using an Inveon SPECT scanner 3, 24, 48, and 168 h after i.v. injection of [125I]-cetuximab or [125I]-IBPA-cetuximab in athymic mice bearing LS174T tumor xenografts. Specific binding and internalized radioactivity of [125I]-IBPA-cetuximab were higher than those of [125I]-cetuximab in PC9, LS174T, and FaDu cell lines. In planar images scant radioactivity was evident in thyroid glands after injection of [125I]-IBPA-cetuximab, while a high level of radioactivity was present in thyroid glands after injection of [125I]-cetuximab. Tumor uptake value of [125I]-IBPA-cetuximab was higher than that of [125I]-cetuximab for up to 168 h. [125I]-IBPA-cetuximab is stable and resistant to deiodination in vivo. IBPA is a promising bi-functional linker for radioiodination of internalizing monoclonal antibodies

  5. Enhanced tumor retention of radioiodinated anti-epidermal growth factor receptor antibody using novel bifunctional iodination linker for radioimmunotherapy

    PubMed Central

    KIM, EUN JUNG; KIM, BYOUNG SOO; CHOI, DAN BEE; CHI, SUNG-GIL; CHOI, TAE HYUN

    2016-01-01

    Radioimmunotherapy (RIT) uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target tumor cells. Radioiodine is most commonly employed to prepare radiolabeled proteins (antibodies, peptides) for in vitro and in vivo applications. A major shortcoming of radioiodinated proteins prepared by direct labeling methods is their deiodination in vivo. For the preparation of more stable radioiodinated antibodies, we developed a new linker (N-(4-isothiocyanatobenzyl)-2-(3-(tributylstannyl)phenyl) acetamide (IBPA). This study evaluated the usefulness of IBPA as a linker for the stable radioiodinated internalizing antibody, cetuximab. Directly labeled cetuximab ([125I]-cetuximab) was prepared by the chloramine T method. To prepare indirectly labeled cetuximab using IBPA ([125I]-IBPA-cetuximab), IBPA was radioiodinated using chloramine-T to give N-(4-isothiocyanatobenzyl)-2-(3-[125I]phenyl)acetamide ([125I]-IBPA), which was purified by high performance liquid chromatography. [125I]-IBPA was then conjugated to cetuximab. In vitro target binding and internalizing assays were performed in PC9, LS174T, and FaDu cell lines. In vivo planar images were obtained using an Inveon SPECT scanner 3, 24, 48, and 168 h after i.v. injection of [125I]-cetuximab or [125I]-IBPA-cetuximab in athymic mice bearing LS174T tumor xenografts. Specific binding and internalized radioactivity of [125I]-IBPA-cetuximab were higher than those of [125I]-cetuximab in PC9, LS174T, and FaDu cell lines. In planar images scant radioactivity was evident in thyroid glands after injection of [125I]-IBPA-cetuximab, while a high level of radioactivity was present in thyroid glands after injection of [125I]-cetuximab. Tumor uptake value of [125I]-IBPA-cetuximab was higher than that of [125I]-cetuximab for up to 168 h. [125I]-IBPA-cetuximab is stable and resistant to deiodination in vivo. IBPA is a promising bi-functional linker for radioiodination of internalizing monoclonal antibodies for in

  6. Discovery – Development of Rituximab

    Cancer.gov

    NCI funded the development of rituximab, one of the first monoclonal antibody cancer treatments. With the discovery of rituximab, more than 70 percent of patients diagnosed with non-hodgkin lymphoma now live five years past their initial diagnosis.

  7. [Rituximab therapy in the treatment of anti-neutrophil cytoplasmic antibody (ANCA) -positive interstitial pneumonia: case report].

    PubMed

    Miyaoka, Tokiko; Itabashi, Mitsuyo; Kumon, Saeko; Akiyama, Kenichi; Iwabuchi, Yuko; Kataoka, Hiroshi; Moriyama, Takahito; Takei, Takashi; Nitta, Kosaku

    2016-01-01

    We report a patient treated with rituximab for interstitial pneumonia (IP) associated with microscopic polyangiitis (MPA) and who was undergoing hemodialysis. A 59-year-old woman who had been treated with tacrolimus for 1 year for rheumatic arthritis was referred to the Department of Nephrology for fatigue, fever, weight loss, and rapidly developing renal dysfunction. On the first admission, severe renal dysfunction, proteinuria, hematuria, and an elevated titer of MPO-ANCA were observed, and the woman was diagnosed with rapidly progressive glomerulonephritis because of MPA. At that point, IP was found to be present but not active. Although steroid semipulse therapy following an initial prednisolone (PSL) administration of 40 mg/day, IVCY, and plasma exchange were administered, renal dysfunction did not recover, and the patient required maintenance hemodialysis. Upon discharge, a high titer of MPO-ANCA was continuously observed. Nine months after the initiation of hemodialysis, respiratory discomfort and desaturation developed. Interstitial shadow and ground glass opacity were seen on a CT scan, and the patient was diagnosed with exacerbation of interstitial pneumonia caused by MPA recurrence. At the second admission, acute findings identified by imaging techniques had improved. However, the high titer of MPO-ANCA continued in spite of the steroid semi-pulse therapy following PSL administration, and rituximab corresponding to 200 mg/weekly for 1 month was also administered. The dose of rituximab was decreased subsequently because the patient was judged to be compromised by the hemodialysis. At the same time, internal administration of sulfamethoxazole/trimethoprim was initiated. After the rituximab treatment, MPO-ANCA antibodies gradually decreased, and the respiratory condition improved. Five months after the rituximab treatment, respiratory dysfunction recurred. Based on the CT findings and a high level of β-D-glycan, the patient was diagnosed with ARDS due to

  8. Labeling of monoclonal antibodies with rhenium-186 using the MAG3 chelate for radioimmunotherapy of cancer: a technical protocol.

    PubMed

    Visser, G W; Gerretsen, M; Herscheid, J D; Snow, G B; van Dongen, G

    1993-11-01

    A detailed technical protocol is provided for reproducible and aseptical production of stable 186Re-monoclonal antibody conjugates. Labeled Mab E48 IgG and its F(ab')2 fragment which are promising candidates for radioimmunotherapy of squamous cell carcinoma of the head and neck were used for evaluation. S-benzoylmercaptoacetyltriglycine (S-benzoyl-MAG3) was used as a precursor. Rhenium-186-MAG3 was prepared via a unique solid-phase synthesis, after which known strategies for esterification and conjugation to Mab IgG/F(ab')2 were applied. The biodistribution of 186Re-E48 F(ab')2 in tumor-bearing nude mice was found to be comparable to that of analogously labeled 99mTc-E48 F(ab')2 or 131I-E48 F(ab')2, indicating that the intrinsic behavior of the antibody remains preserved when using this labeling technique. Radiolytic decomposition of 186Re-E48 IgG/F(ab')2 solutions of 10 mCi.ml-1 was effectively reduced by the antioxidant ascorbic acid. Upon increase of the Re-MAG3 molar amount, a conjugation of seven to eight Re-MAG3 molecules per Mab molecule was generally the maximum ratio that could chemically be obtained. Such a ratio did not impair the immunoreactivity or alter the in vivo biodistribution characteristics of the immunoconjugate, making this labeling procedure suitable for general clinical application. PMID:8229241

  9. Bismuth-212-labeled anti-Tac monoclonal antibody: alpha-particle-emitting radionuclides as modalities for radioimmunotherapy

    SciTech Connect

    Kozak, R.W.; Atcher, R.W.; Gansow, O.A.; Friedman, A.M.; Hines, J.J.; Waldmann, T.A.

    1986-01-01

    Anti-Tac, a monoclonal antibody directed to the human interleukin 2 (IL-2) receptor, has been successfully conjugated to the alpha-particle-emitting radionuclide bismuth-212 by use of a bifunctional ligand, the isobutylcarboxycarbonic anhydride of diethylenetriaminepentaacetic acid. The physical properties of 212Bi are appropriate for radioimmunotherapy in that it has a short half-life, deposits its high energy over a short distance, and can be obtained in large quantities from a radium generator. Antibody specific activities of 1-40 microCi/microgram (1 Ci = 37 GBq) were achieved. Specificity of the 212Bi-labeled anti-Tac was demonstrated for the IL-2 receptor-positive adult T-cell leukemia line HUT-102B2 by protein synthesis inhibition and clonogenic assays. Activity levels of 0.5 microCi or the equivalent of 12 rad/ml of alpha radiation targeted by anti-Tac eliminated greater than 98% the proliferative capabilities of HUT-102B2 cells with more modest effects on IL-2 receptor-negative cell lines. Specific cytotoxicity was blocked by excess unlabeled anti-Tac but not by human IgG. In addition, an irrelevant control monoclonal antibody of the same isotype labeled with 212Bi was unable to target alpha radiation to cell lines. Therefore, 212Bi-labeled anti-Tac is a potentially effective and specific immunocytotoxic reagent for the elimination of IL-2 receptor-positive cells. These experiments thus provide the scientific basis for use of alpha-particle-emitting radionuclides in immunotherapy.

  10. RE-186 labeled 16.88 IgM and 88BV59 IgG human antibody studies to assess potential for radioimmunotherapy

    SciTech Connect

    Breitz, H.; Seiler, C.; Weiden, P. ||

    1994-05-01

    Two studies with Re-186-MAG{sub 2}GABA labeled human antibodies were carried out to assess feasibility for radioimmunotherapy. Antibodies 16.88 and 88BV59 react with different epitopes of CTA 16.88, a tumor associated antigen of colorectal carcinoma. In a phase I dose escalation study, 14 patients received 60 mg/m{sup 2} 16.88 IgM MoAb. The dose of Re-186 ranged from 25 mCi/m{sup 2} to 210 mCi/m{sup 2} divided into 3 weekly infusions. In a pilot study with 88BV59, a human IgG3k MoAb, 20 mg antibody was labeled with 25 mCi/m{sup 2} Re-186 and administered to 4 patients with colon carcinoma. Tumor targeting was seen in 12 of 14 patients with 16.88 and all 4 patients with 88BV59. Retention of antibody at the tumor was longer with 88BV59. One patient developed a rash. No other acute or delayed toxicities were observed. Human anti-human antibody did not develop in any patient. The slower metabolism of the 88BV59 IgG suggests that this form of immunoconjugate merits further investigation for use in radioimmunotherapy.

  11. Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu.

    PubMed Central

    Connett, J M; Anderson, C J; Guo, L W; Schwarz, S W; Zinn, K R; Rogers, B E; Siegel, B A; Philpott, G W; Welch, M J

    1996-01-01

    67Cu (t1/2 = 62 h) has demonstrated potential as a radionuclide for radioimmunotherapy, but limited availability severely restricts its widespread use. 64Cu (t1/2 = 12.8 h) has been shown to have comparable effectiveness in vitro and in vivo. The present study was undertaken to examine the therapeutic potential of 64Cu- and 67Cu-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradeca ne-N, N',N",N"'-tetraacetic acid (BAT)-2-iminothiolane (2IT)-1A3 (1A3 is a mouse anti-human colorectal cancer mAb) for treatment of GW39 human colon carcinoma carried in hamster thighs. Hamsters were injected with 64Cu- or 67Cu-BAT-2IT-1A3 or Cu-labeled nonspecific IgG (MOPC) or saline. Hamsters were killed 6-7 months after therapy or when tumors were > or = 10 g. Of the hamsters with small tumors (mean weight 0.43 +/- 0.25 g), 87.5% were disease-free 7 months after treatment with 2 mCi (1 Ci = 37 GBq) of 64Cu-BAT-2IT-1A3 or 0.4 MCi of 67Cu-BAT-2IT-1A3. The mean tumor doses at these activities of 64Cu- and 67Cu-BAT-2IT-1A3 were 586 and 1269 rad (1 rad = 0.01 Gy), respectively. In contrast, 76% of hamsters treated with 2 mCi of 64Cu-BAT-2IT-MOPC or 0.4 mCi of 67Cu-BAT-2IT-MOPC had to be killed before 6 months because of tumor regrowth. When hamsters with larger tumors (mean weight 0.66 +/- 0.11 g) were treated with 64Cu- or 67Cu-BAT-2IT-1A3, survival was extended compared with controls, but only one animal remained tumor-free to 6 months. These results demonstrate that 64Cu- and 67Cu-BAT-2IT-1A3 given in a single administered dose can eradicate small tumors without significant host toxicity, but additional strategies to deliver higher tumor doses will be needed for larger tumors. PMID:8692901

  12. Pretargeted Imaging and Radioimmunotherapy of Cancer Using Antibodies and Bioorthogonal Chemistry

    PubMed Central

    van de Watering, Floor C. J.; Rijpkema, Mark; Robillard, Marc; Oyen, Wim J. G.; Boerman, Otto C.

    2014-01-01

    Selective delivery of radionuclides to tumors may be accomplished using a two-step approach, in which in the first step the tumor is pretargeted with an unlabeled antibody construct and in the second step the tumor is targeted with a radiolabeled small molecule. This results in a more rapid clearance of the radioactivity from normal tissues due to the fast pharmacokinetics of the small molecule as compared to antibodies. In the last decade, several pretargeting approaches have been tested, which have shown improved tumor-to-background ratios and thus improved imaging and therapy as compared to directly labeled antibodies. In this review, we will discuss the strategies and applications in (pre-)clinical studies of pretargeting concepts based on the use of bispecific antibodies, which are capable of binding to both a target antigen and a radiolabeled peptide. So far, three generations of the bispecific antibody-based pretargeting approach have been studied. The first clinical studies have shown the feasibility and potential for these pretargeting systems to detect and treat tumor lesions. However, to fully integrate the pretargeting approach in clinic, further research should focus on the best regime and pretargeting protocol. Additionally, recent developments in the use of bioorthogonal chemistry for pretargeting of tumors suggest that this chemical pretargeting approach is an attractive alternative strategy for the detection and treatment of tumor lesions. PMID:25593917

  13. Pretargeted imaging and radioimmunotherapy of cancer using antibodies and bioorthogonal chemistry.

    PubMed

    van de Watering, Floor C J; Rijpkema, Mark; Robillard, Marc; Oyen, Wim J G; Boerman, Otto C

    2014-01-01

    Selective delivery of radionuclides to tumors may be accomplished using a two-step approach, in which in the first step the tumor is pretargeted with an unlabeled antibody construct and in the second step the tumor is targeted with a radiolabeled small molecule. This results in a more rapid clearance of the radioactivity from normal tissues due to the fast pharmacokinetics of the small molecule as compared to antibodies. In the last decade, several pretargeting approaches have been tested, which have shown improved tumor-to-background ratios and thus improved imaging and therapy as compared to directly labeled antibodies. In this review, we will discuss the strategies and applications in (pre-)clinical studies of pretargeting concepts based on the use of bispecific antibodies, which are capable of binding to both a target antigen and a radiolabeled peptide. So far, three generations of the bispecific antibody-based pretargeting approach have been studied. The first clinical studies have shown the feasibility and potential for these pretargeting systems to detect and treat tumor lesions. However, to fully integrate the pretargeting approach in clinic, further research should focus on the best regime and pretargeting protocol. Additionally, recent developments in the use of bioorthogonal chemistry for pretargeting of tumors suggest that this chemical pretargeting approach is an attractive alternative strategy for the detection and treatment of tumor lesions. PMID:25593917

  14. Pretargeted Radioimmunotherapy Using Anti-CD45 Monoclonal Antibodies to Deliver Radiation to Murine Hematolymphoid Tissues and Human Myeloid Leukemia

    SciTech Connect

    Pagel, John M.; Matthews, Dana C.; Kenoyer, Aimee L.; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Gopal, Ajay K.; Lin, Yukang; Saganic, Laura; Appelbaum, Frederick R.; Press, Oliver W.

    2009-01-01

    The efficacy of radioimmunotherapy (RIT) for treatment of patients with hematological malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted RIT studies to augment the efficacy in mice of therapy using a pretargeted anti-human (h)CD45 antibody (Ab)-streptavidin (SA) conjugate followed by delivery of a biotinylated clearing agent and radiolabeled-DOTA-biotin. Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and <1:1 with conventional RIT. In vivo imaging studies confirmed that the pretargeted RIT approach provided high-contrast tumor images with minimal blood-pool activity, whereas directly-labeled anti-hCD45 Ab produced distinct tumor images but the blood pool retained a large amount of labeled antibody for a prolonged time. Therapy experiments demonstrated that 90Y-DOTA-biotin significantly prolonged survival of mice treated pretargeted with anti-hCD45 Ab-SA compared to mice treated with conventional RIT using 90Y-labeled anti-hCD45 Ab at the maximally tolerated dose (400 µCi). Since human CD45 antigens are confined to xenograft tumor cells in this model, and all murine tissues are devoid of hCD45 and will not bind anti-hCD45 Ab, we also compared one-step and pretargeted RIT using an anti-murine (m)CD45 Ab (A20 ) in a model where the target antigen is present on normal hematopoietic tissues. After 24 hours, 27.3 ± 2.8% of the injected dose of radionuclide was delivered per gram (% ID/g) of lymph node using 131I-A20-Ab compared with 40.0 ± 5.4% ID/g for pretargeted 111In-DOTA-biotin (p value). These data suggest that multi-step pretargeted methods for delivering RIT are superior to conventional RIT when targeting CD45 for the treatment of leukemia and may allow for the intensification of therapy, while minimizing toxicities.

  15. Radioimmunotherapy of human tumours.

    PubMed

    Larson, Steven M; Carrasquillo, Jorge A; Cheung, Nai-Kong V; Press, Oliver W

    2015-06-01

    The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types. PMID:25998714

  16. Curative radioimmunotherapy of human mammary carcinoma xenografts with iodine-131-labeled monoclonal antibodies

    SciTech Connect

    Senekowitsch, R.; Reidel, G.; Moellenstaedt, S.Kr.; Kriegel, H.; Pabst, H.W. )

    1989-04-01

    The radioiodinated monoclonal antibody BW 495/36 showed an exceptionally high uptake and long residence time in human ductal mammary carcinoma xenografts in nude mice. There was a mean tumor uptake of 82%/g 24 hr p.i., decreasing with a biologic half-life of approximately 6 days, to 15%/g by Day 16. The tumor-to-blood ratio increased from 2.8 to 21.4 and the percentage of the whole-body retention recovered in the tumor from 47% to 80% during the same time interval. The therapeutic efficiency of two injections of 7.4 MBq {sup 131}I-BW 495/36 was evaluated by comparing the tumor size with that in mice injected with either the same amount of the unlabeled MoAb, the same radioactivity of an {sup 131}I-labeled nonspecific MoAb, or with saline only. The high tumor accumulation of {sup 131}I-BW 495/36 led to a total tumor dose of 77 Gy resulting in a mean reduction in tumor diameter of 50%, corresponding to a reduction in tumor volume of 88% within 42 days p.i. Unlabeled MoAb had no effect on tumor growth compared with controls, whereas {sup 131}I nonspecific antibody caused a slight inhibition of tumor growth. Histologic tumor sections showed large areas of necrosis and a pronounced vacuolation of the tumor cell cytoplasm between Days 7 and 30 p.i. By Day 42 all remaining tissue in the tumor was identified as mouse connective tissue.

  17. Radioimmunotherapy of lymphoma: Bexxar and Zevalin.

    PubMed

    Goldsmith, Stanley J

    2010-03-01

    Radioimmunotherapy is a form of targeted radionuclide therapy that uses a monoclonal antibody to deliver localized radiation. It is most appropriate for treatment of multiple tumor sites that cannot be readily excised surgically or irradiated using external beam radiation or brachytherapy. At present, 2 products, Bexxar ((131)I-tositumomab and unlabeled tositumomab, GlaxoSmithKline, Triangle Park, NC) and Zevalin ((90)Y-ibritumomab tiuxetan and unlabeled rituximab, Spectrum Pharmaceuticals, Irvine, CA and Cell Therapeutics, Seattle, WA) are approved for treatment of non-Hodgkin's lymphoma in certain clinical situations in the United States and Canada. Zevalin is available also in Europe, and there are plans to make both agents more widely available. The therapeutic dose to be used depends upon a number of patient-specific variables. Both regimen achieve a complete response or partial response in approximately 3 of 4 patients, with a duration of remission lasting many years in some cases. This article reviews the basis for dose selection, the nuclear medicine procedures involved, the results obtained to date, and issues related to patient and staff safety. PMID:20113680

  18. Rituximab: Uses in Dermatology.

    PubMed

    Gleghorn, K; Wilson, J; Wilkerson, M

    2016-09-01

    Rituximab is an anti-CD20 monoclonal antibody with considerable potential in dermatology due to an increase in off-label indications. Chronic graft-versus-host disease and pemphigus vulgaris are two of the most promising indications for off-label use of rituximab. It is a generally safe alternative that should be considered when traditional therapy with corticosteroids or immunosuppressants has failed or caused significant intolerance. Currently, rituximab is only FDA-approved for treatment of follicular and diffuse large B-cell non-Hodgkin's lymphoma, rheumatoid arthritis, chronic lymphocytic leukemia, granulomatosis with polyangiitis (formerly Wegener's granulomatosis) and microscopic polyangiitis. Herein, off-label uses of rituximab and its efficacy in the treatment of cutaneous diseases are reviewed. PMID:27603326

  19. Immune-mediated necrotising myopathy associated with antibodies to the signal recognition particle treated with a combination of rituximab and cyclophosphamide.

    PubMed

    Fernandes das Neves, Marisa; Caetano, Joana; Oliveira, Susana; Delgado Alves, José

    2015-01-01

    A 50-year-old man presented with dysphagia and proximal muscle weakness. He was diagnosed with immune-mediated necrotising myopathy associated with antibodies to the signal recognition particle. After an initial response following treatment with high-dose steroids, intravenous immunoglobulin and methotrexate, there was a relapse of the immune condition. The clinical deterioration occurred less than 2 months after disease onset. The refractoriness of this disease was characterised by an increase of the already severe muscle wasting that led to respiratory failure and progressive dysphagia, regardless of the immunosuppressant treatment. At this time the patient was referred to our department. He was restarted on intravenous pulses of methylprednisolone associated with intravenous cyclophosphamide, but with no effect. After 3 weeks, rituximab was started with a dramatic and progressive improvement. There were no complications associated with rituximab/cyclophosphamide treatment and the disease has been kept in remission, for the last 3 years. PMID:26240092

  20. Radiometals as payloads for radioimmunotherapy for lymphoma.

    PubMed

    DeNardo, Gerald L; Kennel, Stephen J; Siegel, Jeffry A; Denardo, Sally J

    2004-10-01

    Because of their remarkable effectiveness in radioimmunotherapy (RIT), 2 anti-CD20 monoclonal antibody (MAb) drugs, one labeled with indium 111 for imaging or yttrium 90 for therapy, and another labeled with iodine I 131 for imaging and therapy, have been approved for use in patients with non-Hodgkin's lymphoma (NHL). Successful RIT for lymphomas is due in large part to the rapid and efficient binding of the targeted MAb to lymphoma cells. Carcinomas are more difficult to access, necessitating novel strategies matched with radionuclides with specific physical properties. Because there are many radionuclides from which to choose, a systematic approach is required to select those preferred for a specific application. Thus far, radionuclides with g emissions for imaging and particulate emissions for therapy have been investigated. Radionuclides of iodine were the first to be used for RIT. Many conventionally radioiodinated MAbs are degraded after endocytosis by target cells, releasing radioiodinated peptides and amino acids. In contrast, radiometals have been shown to have residualizing properties, advantageous when the MAb is localized in malignant tissue. b-emitting lanthanides like those of 90Y, lutetium 177, etc. have attractive combinations of biologic, physical, radiochemical, production, economic, and radiation safety characteristics. Other radiometals, such as copper-67 and copper-64, are also of interest. a-emitters, including actinium-225 and bismuth-213, have been used for therapy in selected applications. Evidence for the impact of the radionuclide is provided by data from the randomized pivotal phase III trial of 90Y ibritumomab tiuxetan (Zevalin) in patients with NHL; responses were about 2 times greater in the 90Y ibritumomab tiuxetan arm than in the rituximab arm. It is clear that RIT has emerged as a safe and efficient method for treatment of NHL, especially in specific settings. PMID:15498149

  1. V gamma 9 V delta 2 T cell cytotoxicity against tumor cells is enhanced by monoclonal antibody drugs--rituximab and trastuzumab.

    PubMed

    Tokuyama, Hirotake; Hagi, Tomomi; Mattarollo, Stephen R; Morley, Jacqueline; Wang, Qiao; So, Hang-Fai; Fai-So, Hang; Moriyasu, Fuminori; Nieda, Mie; Nicol, Andrew J

    2008-06-01

    V gamma 9 V delta 2 T cells exert potent cytotoxicity toward various tumor cells and adoptive transfer of V gamma 9 V delta 2 T cells is an attractive proposition for cell based immunotherapy. V gamma 9 V delta 2 T cells expanded in the presence of Zoledronate and IL-2 express CD16 (Fc gamma RIII), which raises the possibility that V gamma 9 V delta 2 T cells could be used in conjunction with tumor targeting monoclonal antibody drugs to increase antitumor cytotoxicity by antibody dependent cellular cytotoxicity (ADCC). Cytotoxic activity against CD20-positive B lineage lymphoma or chronic lymphocytic leukemia (CLL) and HER2-positive breast cancer cells was assessed in the presence of rituximab and trastuzumab, respectively. Cytotoxicity of V gamma 9 V delta 2 T cells against CD20-positive targets was higher when used in combination with rituximab. Similarly, V gamma 9 V delta 2 T cells used in combination with trastuzumab resulted in greater cytotoxicity against HER2-positive cells in comparison with either agent alone and this effect was restricted to the CD16(+)V gamma 9 V delta 2 T cell population. Our results show that CD16(+)V gamma 9 V delta 2 T cells recognize monoclonal antibody coated tumor cells via CD16 and exert ADCC similar to that observed with NK cells, even when target cells are relatively resistant to monoclonal antibodies or V gamma 9 V delta 2 T cells alone. Combination therapy involving ex vivo expanded CD16(+)V gamma 9 V delta 2 T cells and monoclonal antibodies may enhance the clinical outcomes for patients treated with monoclonal antibody therapy. PMID:18307255

  2. Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis.

    PubMed

    Koo, Yu Xuan; Tay, Matthew; Teh, Yii Ean; Teng, David; Tan, Daniel S W; Tan, Iain B H; Tai, David W M; Quek, Richard; Tao, Miriam; Lim, Soon Thye

    2011-10-01

    The use of rituximab has been associated with increased risk of hepatitis B virus (HBV) reactivation in patients who are hepatitis B surface antigen (HBsAg) negative and antihepatitis B core antibody (anti-HBc) positive. We aim to determine the rate of HBV reactivation in this group of patients who received rituximab-containing combination chemotherapy without concomitant antiviral prophylaxis and to identify potential risk factors for reactivation. Sixty-two HBsAg negative/anti-HBc positive patients with B-cell lymphoma treated with rituximab-based immunochemotherapy from 2006 to 2009 were included. None of the patients received concomitant antiviral prophylaxis. In this cohort, 48 (77%) patients received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), eight (13%) received rituximab with cyclophosphamide, vincristine and prednisolone, and six (10%) received other chemotherapy regimens. Two patients suffered HBV reactivation; both were above 70 years of age, received R-CHOP chemotherapy and were negative for antihepatitis B surface antibody (anti-HBs) at baseline. One of the two patients reactivated shortly after completion of R-CHOP chemotherapy while the other reactivated during rituximab maintenance treatment. Thus, the overall reactivation rate in this cohort of patients is 3% (2/62), 4% (2/48), and 25% (1/4) in patients who received R-CHOP chemotherapy and who received rituximab maintenance, respectively. The rate of HBV reactivation is low in patients who are HBsAg negative/anti-HBc positive receiving rituximab-based combination chemotherapy without concomitant antiviral prophylaxis. However, elderly patients, particularly those without anti-HBs, seemed particularly at risk. PMID:21520001

  3. Radioimmunotherapy with [188Re]-labelled anti-CD66 antibody in the conditioning for allogeneic stem cell transplantation for high-risk acute myeloid leukemia.

    PubMed

    Koenecke, Christian; Hofmann, Michael; Bolte, Oliver; Gielow, Peter; Dammann, Elke; Stadler, Michael; Franzke, Anke; Boerner, Anne Rose; Eder, Matthias; Ganser, Arnold; Knapp, Wolfram; Hertenstein, Bernd

    2008-05-01

    Between July 2000 and June 2003 a total of 21 patients with high-risk acute myeloid leukemia (AML; n = 14), AML after myelodysplastic syndrome (MDS; n = 6) or advanced MDS (n = 1) were treated with an 188-Re labelled anti-CD66 antibody in the conditioning regimen for allogeneic stem cell transplantation. Radioimmunotherapy (RIT) was followed by standard full-dose conditioning with busulfan and high-dose cyclophosphamide in 11 patients and reduced intensity conditioning regimen in 10 patients. All patients received an unmanipulated allogeneic graft from alternative donors (n = 15) or a HLA-identical familiy donor (n = 6). With a median follow up of 42 months (23-60) disease free survival for all patients was 43%. Nine patients are still alive and in ongoing complete hematological remission. The treatment related mortality was 28.6% (n = 6) and an equal number of patients died of relapsing disease within 30-385 days after transplantation. Late organ toxicity, monitored for more than 1 year, was mild and not clinically relevant. The combination of RIT with chemotherapeutic conditioning seems to be a therapy with an acceptable risk of treatment related morbidity and mortality as well as occurrence of severe acute GvHD. PMID:18415659

  4. Radioimmunotherapy of Metastatic Prostate Cancer with ¹⁷⁷Lu-DOTAhuJ591 Anti Prostate Specific Membrane Antigen Specific Monoclonal Antibody.

    PubMed

    Vallabhajosula, Shankar; Nikolopoulou, Anastasia; Jhanwar, Yuliya S; Kaur, Gurveen; Tagawa, Scott T; Nanus, David M; Bander, Neil H; Goldsmith, Stanley J

    2016-01-01

    Prostate specific membrane antigen (PSMA) is the single most well-validated prostate cancer (PCa)-specific cell membrane antigen known. It is present in high levels in 95% of PCa, and is an ideal target to develop radiopharmaceuticals for imaging studies and radionuclide therapy. Humanized J591 monoclonal antibody (mAb) binds specifically with nanomolar affinity to the extracellular domain of PSMA. After binding, the PSMA-antibody complex is rapidly internalized, increasing the potential utility of PSMA as a target for the delivery of mAb-conjugated radionuclides or cytotoxins. J591 mAb was labeled with 177Lu at a high specific activity (10-30 mCi/mg) using DOTA as the bifunctional chelate. The preclinical data in PSMA positive xenografts, strongly suggested that 177;Lu-J591 mAb is an ideal radiopharmaceutical for RIT of metastatic PCa. Since October 2000, five clinical studies (phase I and II) were performed in subjects with metastatic castration-resistant prostate cancer (CRPC) using 177Lu-J591. The methodology and the results of these clinical studies are briefly reviewed in this article. The maximum tolerated dose (MTD) as a single dose was 70 mCi2. Based on dose fractionation (DF), MTD was 90 mCi/m2(2 doses of 45 mCi/m2, 2 wks apart). Phase II study in patients with progressive metastatic CRPC, at a dose of 65- 70 mCi/m2 resulted in significant PSA declines in 60% of the patients. While myelosuppression was the dose limiting toxicity, DF alone or in combination with docetaxel also resulted in significant PSA declines with much less toxicity. 177Lu imaging studies demonstrated accurate targeting of known metastatic sites in >90% of patients and those with stronger PSMA expression by semi-quantitative imaging had more PSA declines. These clinical studies clearly documented the potential therapeutic value of radioimmunotherapy (RIT) in metastatic PCa. PMID:25771365

  5. Radioimmunotherapy of infectious diseases

    PubMed Central

    Dadachova, Ekaterina; Casadevall, Arturo

    2009-01-01

    The need for novel approaches to treat infectious diseases is obvious and urgent. This situation has renewed interest in using monoclonal antibodies (mAbs) in therapy of infectious diseases. During the last 5 years radioimmunotherapy (RIT), a modality developed for cancer treatment, has been successfully adapted for the treatment of experimental fungal (C. neoformans and H. capsulatum), bacterial (S. pneumoniae and B. anthracis) and viral (HIV-1) infections. RIT produced none or only transient hematological toxicity in experimental animals. Investigation of radiobiological mechanisms of RIT of infections showed that microbial cells are killed by both "direct hit" and "cross-fire" radiation. MAbs radiolabeled with either alpha- or beta-emitters stimulated apoptosis-like cell death, while only mAbs radiolabeled with alpha-emitter 213Bi also decreased the metabolic activity of microbial cells. The success of this approach in laboratory studies combined with earlier nuclear medicine experience on pre-clinical and clinical studies utilizing radiolabeled organism-specific antibodies for imaging of infections provides encouragement for feasibility of therapeutically targeting microbes with labeled antibodies. We envision that first the organism-specific mAbs will be radiolabeled with imaging radionuclides such as 99mTc or 111In to localize the sites of infection with SPECT followed by RIT with 188Re- or 90Y-labeled mAb, respectively. Also, immunoPET might be utilized for imaging of infection before treatment if such positron-emitting radionuclides as 86Y (matching pair for 90Y) or 124I (matching pair for 131I) are available. It might be possible to create a so-called “pan-antibody” which would recognize an antigen shared by a particular class of human pathogens such as fungi, for example. The availability of such antibodies would eliminate the necessity of having antibodies specific for each particular microorganism and would enormously enhance the development of RIT

  6. Comparability analysis of anti-CD20 commercial (rituximab) and RNAi-mediated fucosylated antibodies by two LC-MS approaches

    PubMed Central

    Li, Chen; Rossomando, Anthony; Wu, Shiaw-Lin; Karger, Barry L.

    2013-01-01

    In developing biosimilar or biobetter products, comparability to the reference product is required to claim similar integrity or intended purpose. In this work, an anti-CD20 monoclonal antibody developed using RNA interference to decrease core fucosylation (RNAi-mediated) was comprehensively characterized by LC-MS and compared with the commercially-available anti-CD20 rituximab (MabThera®). As anticipated, < 30% core fucose was found within the RNAi-produced molecule (compared with > 90% in rituximab), and the reduction in fucose resulting in a significant improvement in FcγRΙΙΙa binding and antibody-dependent cell-mediated cytotoxicity. Two mutations, S258Y (fully mutated) and F174I/L (partially mutated), however, were detected in the production of the RNAi-mediated molecule. An alternative LC-MS approach using dimethyl labeling (i.e., 2CH2 for rituximab and 2CD2 for the RNAi-mediated molecule) was developed to additionally compare the two mAbs and confirm the full sequence with the two mutation sites. Furthermore, disulfide linkages were found to be the same for the two antibodies, with a small portion of unpaired cysteines in both products. Disulfides were correctly linked if the samples were prepared at low pH (i.e., enzymatic digestion by pepsin at pH 2); however, trace amounts of scrambling were found by trypsin digestion at pH 6.8, and this scrambling increased significantly at pH 8. Typical modifications, such as pyro-Glu formation at the N-terminus, K clipping at the C-terminus, oxidation at Met, and deamidation at Asn, were also detected with no significant differences between the two products. Using the LC-MS approaches for the comparability study, product integrity with critical structure information was revealed for confirmation of intended purpose (core fucosylation), identification of critical parameters (e.g., sample pH), and correction as needed (amino acid mutation). PMID:23751726

  7. Yttrium-90-ibritumomab tiuxetan radioimmunotherapy: a new treatment approach for B-cell non-Hodgkin's lymphoma.

    PubMed

    Witzig, Thomas E

    2004-02-01

    either rituximab or ibritumomab tiuxetan. The aim was to demonstrate that the addition of the yttrium-90 radioisotope to the antibody provided additional efficacy over the unconjugated ("cold") rituximab alone. The results of this study showed an overall response rate of 80% with (90)Y-ibritumomab tiuxetan versus 56% for rituximab (p = 0.002). An additional trial enrolled 54 patients who were nonresponsive or refractory to rituximab and treated the patients with a single dose of 0.4 mCi/kg (90)Y-ibritumomab tiuxetan. An overall response rate of 74% was found in these rituximab-refractory patients. These data provide further evidence of the added value of the yttrium-90. Finally, a fifth trial treated 30 patients with mild thrombocytopenia using 0.3 mCi/kg (90)Y-ibritumomab tiuxetan and found an overall response rate of 83%. (90)Y-ibritumomab tiuxetan radioimmunotherapy is a new treatment modality for patients with relapsed B-cell non-Hodgkin's lymphoma. The advantages of this therapy are that it utilizes targeted radiation in a single-dose, outpatient schedule that is well tolerated and accepted by the patient. Future trials will build on these results and determine at what point in the disease course this modality can best be utilized to maximize the benefits to the patient. PMID:15045033

  8. Radioimmunotherapy of human head and neck squamous cell carcinoma xenografts with 131I-labelled monoclonal antibody E48 IgG.

    PubMed Central

    Gerretsen, M.; Schrijvers, A. H.; van Walsum, M.; Braakhuis, B. J.; Quak, J. J.; Meijer, C. J.; Snow, G. B.; van Dongen, G. A.

    1992-01-01

    Monoclonal antibody (MAb) E48 reacts with a 22 kD antigen exclusively expressed in squamous and transitional epithelia and their neoplastic counterparts. Radiolabelled with 99mTc, MAb E48 is capable of targeting metastatic and recurrent disease in patients with head and neck cancer. In this study, the capacity of 131I-labelled MAb E48 to eradicate xenografts of human squamous cell carcinoma of the head and neck (HNSCC) in nude mice was examined. Experimental groups received a single i.v. bolus injection of 400 microCi MAb E48 IgG (number of mice (n = 6, number of tumours (t) = 9) or 800 microCi MAb E48 IgG (n) = 5,t = 7), whereas control groups received either diluent (n = 3,t = 5), unlabelled MAb E48 IgG (n = 4,t = 5) or 800 microCi 131I-labelled isotype-matched control MAb (n = 6,t = 9). A 4.1-fold increase in the median tumour volume doubling time and regression of two out of ten tumours (20%) was observed in mice treated with 400 microCi. In mice treated with 800 microCi. In mice treated with 800 microCi, two out of seven tumours (29%) showed complete remission without regrowth during follow-up (greater than 3 months). Median tumour volume doubling time in the remaining five tumours was increased 7.8-fold. No antitumour effects were observed in mice injected with diluent, unlabelled MAb E48 or 131I-labelled control MAb. In the same xenograft model, chemotherapy with doxorubicin, 5-fluorouracil, cisplatin, bleomycin, methotrexate or 2',2'-difluorodeoxycytidine yielded a less profound effect on tumour volume doubling time. Increases in tumour volume doubling time with these chemotherapeutic agents were 4, 2.2, 2.1, 1.7, 0, and 2.6 respectively. Moreover, no cures were observed with any of these chemotherapeutic agents. From the tissue distribution of 800 microCi MAb E48, the absorbed cumulative radiation doses of tumour and various organs were calculated using the trapezoid integration method for the area under the curve. To tumour xenografts, 12,170 cGy was

  9. Pretargeted Radioimmunotherapy of Prostate Cancer with an Anti-TROP-2×Anti-HSG Bispecific Antibody and a 177Lu-Labeled Peptide

    PubMed Central

    Frielink, Cathelijne; Goldenberg, David M.; Sharkey, Robert M.; Lütje, Susanne; McBride, William J.; Oyen, Wim J.G.; Boerman, Otto C.

    2014-01-01

    Abstract TROP-2 is a pancarcinoma marker that is expressed at high levels in many epithelial cancers, including prostate cancer (PC). The trivalent bispecific antibody TF12 (anti-TROP2×anti-HSG [histamine-succinyl-glycine]) has shown to effectively target PC. In this study, the efficacy of pretargeted radioimmunotherapy (PRIT) with multiple cycles of TF12 and 177Lu-labeled diHSG-peptide (IMP288) in mice with s.c. PC3 tumors was investigated and compared with that of conventional RIT with 177Lu-labeled anti-TROP-2 mAb hRS7. Methods: The potential of one, two, and three cycles of PRIT using the TF12 pretargeted 177Lu-IMP288 (41 MBq per cycle) was determined in mice with s.c. PC3 tumors, and compared with the efficacy and toxicity of RIT with 177Lu-hRS7 dosed at the maximum tolerated dose (11 MBq). Results: PRIT of two and three cycles showed significantly higher median survival (>150 days) compared with PRIT of one cycle of TF12 and 177Lu-IMP288 (111 days, p<0.001) or the controls (76 days, p<0.0001). All mice treated with the mAb 177Lu-hRS7 survived at the end of the experiment (150 days), compared with 80% in the mice that were treated with three cycles of PRIT and 70% in the group that received two cycles of PRIT. Clinically significant hematologic toxicity was found only in the groups that received either three cycles of PRIT (p<0.0009) or RIT (p<0.0001). Conclusions: TROP-2-expressing PC can be targeted efficiently with TF12 and radiolabeled IMP288. 177Lu-IMP288 accumulated rapidly in the tumors. PRIT of multiple cycles inhibited the growth of s.c. PC3 tumors. Clinically relevant hematological toxicity was observed in the group that received three cycles of PRIT; however, conventional RIT with the parent mAb 177Lu-hRS7 was at least as effective with similar toxicity. PMID:25226447

  10. A 90Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy

    PubMed Central

    2014-01-01

    Background ROBO1 is a membrane protein that functions in axon guidance. ROBO1 contributes to tumour metastasis and angiogenesis and may have potential as a target protein of immunotherapy because ROBO1 is specifically expressed at high levels in hepatocellular carcinoma. In this study, we examined biodistribution and radioimmunotherapy (RIT) using a radioisotope-labelled anti-ROBO1 monoclonal antibody (MAb) against hepatocellular carcinoma models. Methods ROBO1-positive HepG2 human hepatocellular carcinoma xenograft nude mice were used in this study. We conjugated anti-ROBO1 MAb with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and the conjugates were labelled with 111In and 90Y. To study biodistribution, the 111In-DOTA-anti-ROBO1 MAb was injected into HepG2 xenograft mice via the tail vein. To evaluate any antitumour effect, a RIT study was performed, and the 90Y-DOTA-anti-ROBO1 MAb was injected via the tail vein. Tumour volume, mouse weight, and blood cell count were periodically measured throughout the experiments. The tumours and organs of mice were collected, and a histopathological analysis was carried out. Results The tumour uptake of 111In-anti-ROBO1 MAb in HepG2 xenograft mice was 15.0% ± 0.69% injected dose per gram at 48 h after injection. Immunotherapy with cold-anti-ROBO1 MAb (70 μg) did not cause a significant antitumour effect. RIT with 6.7 MBq of 90Y-anti-ROBO1 MAb caused significant tumour growth suppression. Transient body weight loss and bone-marrow suppression were observed. Histopathological analyses of tumours revealed the fatal degeneration of tumour cells, significant reduction of the Ki-67 index, and an increase of the apoptosis index. Normal organs showed no significant injury, but a transient reduction of hematopoietic cells was observed in the spleen and in the sternal bone marrow. Conclusions These results suggest that RIT with 90Y-anti-ROBO1 MAb is a promising treatment for ROBO1-positive hepatocellular

  11. Radiolanthanide-labeled monoclonal antibody CC49 for radioimmunotherapy of cancer: biological comparison of DOTA conjugates and 149Pm, 166Ho, and 177Lu.

    PubMed

    Mohsin, Huma; Jia, Fang; Sivaguru, Geethapriya; Hudson, Michael J; Shelton, Tiffani D; Hoffman, Timothy J; Cutler, Cathy S; Ketring, Alan R; Athey, Phillip S; Simón, Jaime; Frank, R Keith; Jurisson, Silvia S; Lewis, Michael R

    2006-01-01

    The radiolanthanides 149Pm, 166Ho, and 177Lu have decay characteristics suitable for radioimmunotherapy (RIT) of cancer. N-Hydroxysulfosuccinimidyl DOTA (DOTA-OSSu) and methoxy-DOTA (MeO-DOTA) were conjugated to the anti-TAG-72 monoclonal antibody CC49 for radiolabeling with 149Pm, 166Ho, and 177Lu. While both DOTA conjugates could be labeled to high specific activity with 177Lu, MeO-DOTA afforded superior conjugate stability, radiolabeling, and radiochemical purity. Pilot biodistributions in nude mice bearing LS174T human colon carcinoma xenografts demonstrated that MeO-DOTA afforded higher tumor uptake and lower kidney retention of 177Lu than DOTA-OSSu. The in vitro stability of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 was evaluated using serum and hydroxyapatite assays. Serum stability of radiolanthanide-labeled MeO-DOTA-CC49 followed a trend based on the coordination energies of the radiometals, with 177Lu showing the highest stability after 96 to 168 h at 37 C. In contrast, MeO-DOTA-CC49 labeled with all three radiolanthanides was >92% stable to hydroxyapatite challenge for 168 h at 37 C. Comprehensive biodistributions of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 were obtained in LS174T-bearing nude mice. Maximum tumor uptakes were 100.0% ID/g for 149Pm at 96 h, 69.5% ID/g for 166Ho at 96 h, and 132.4% ID/g for 177Lu at 168 h. Normal organ uptakes were generally low, except in the liver, spleen, and kidney at early time points. By 96 to 168 h postinjection, nontarget organ uptake decreased to approximately 7% ID/g (kidney), 12% ID/g (spleen), and 20% ID/g (liver) for each radiolanthanide. When labeled with 149Pm, 166Ho, and 177Lu, MeO-DOTA-CC49 has potential for RIT of colorectal cancer and other carcinomas. PMID:16536481

  12. Improved radioimmunotherapy of hematologic malignancies

    SciTech Connect

    Press, O.W.

    1992-03-24

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides ({sup 131}Iodine, {sup 111}Indium, {sup 90}Yttrium, {sup 99m}Technetium, {sup 186}Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer.

  13. Improved radioimmunotherapy of hematologic malignancies. Final technical report

    SciTech Connect

    Press, O.W.

    1996-08-15

    Experiments were performed to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells. An attempt was made to examine in vivo the effects of lysosomotropic amines and thioamides on the retention of radiolabeled monoclonal antibodies by tumor cells. Experiments also examined the impact of newer radioiodination techniques on the metabolic degradation of radioiodinated antibodies, and on the radioimmunoscintigraphy and radioimmunotherapy of neoplasms. The endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with I-131, In-111, and Y-90 were compared. The utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer was investigated.

  14. Radioimmunotherapy with alpha-particle emitting radionuclides.

    PubMed

    Zalutsky, M R; Pozzi, O R

    2004-12-01

    An important consideration in the development of effective strategies for radioimmunotherapy is the nature of the radiation emitted by the radionuclide. Radionuclides decaying by the emission of alpha-particles offer the possibility of matching the cell specific reactivity of monoclonal antibodies with radiation with a range of only a few cell diameters. Furthermore, alpha-particles have important biological advantages compared with external beam radiation and beta-particles including a higher biological effectiveness, which is nearly independent of oxygen concentration, dose rate and cell cycle position. In this review, the clinical settings most likely to benefit from alpha-particle radioimmunotherapy will be discussed. The current status of preclinical and clinical research with antibodies labeled with 3 promising alpha-particle emitting radionuclides - (213)Bi, (225)Ac, and (211)At - also will be summarized. PMID:15640792

  15. The La antigen is over-expressed in lung cancer and is a selective dead cancer cell target for radioimmunotherapy using the La-specific antibody APOMAB®

    PubMed Central

    2014-01-01

    Background The lupus-associated (La)-specific murine monoclonal antibody DAB4 (APOMAB®) specifically binds dead cancer cells. Using DAB4, we examined La expression in human lung cancer samples to assess its suitability as a cancer-selective therapeutic target. We evaluated the safety and effectiveness of radioimmunotherapy (RIT) using DAB4 radiolabeled with Lutetium-177 (177Lu) in the murine Lewis Lung (LL2) carcinoma model, and determined whether combining RIT with DNA-damaging cisplatin-based chemotherapy, a PARP inhibitor (PARPi), or both alters treatment responses. Methods The expression of La mRNA in human lung cancer samples was analysed using the online database Oncomine, and the protein expression of La was examined using a TissueFocus Cancer Survey Tissue Microarray. The binding of DAB4 to cisplatin-treated LL2 cells was assessed in vitro. LL2 tumour-bearing mice were administered escalating doses of 177Lu-DAB4 alone or in combination with chemotherapy, and tumour growth and survival measured. Biodistribution analysis was used to determine tissue uptake of 177Lu-DAB4 or its isotype control (177Lu-Sal5), when delivered alone or after chemotherapy. PARPi (rucaparib; AG-014699) was combined with chemotherapy and the effects of combined treatment on tumour growth, tumour cell DNA damage and death, and intratumoural DAB4 binding were also analysed. The effect of the triple combination of PARPi, chemotherapy and 177Lu-DAB4 on tumour growth and survival of LL2 tumour-bearing mice was tested. Results La was over-expressed at both mRNA and protein levels in surgical specimens of human lung cancer and the over-expression of La mRNA conferred a poorer prognosis. DAB4 bound specifically to cisplatin-induced dead LL2 cells in vitro. An anti-tumour dose response was observed when escalating doses of 177Lu-DAB4 were delivered in vivo, with supra-additive responses observed when chemotherapy was combined with 177Lu-DAB4. Combining PARPi with chemotherapy was more

  16. Radioimmunotherapy and Autologous Stem-Cell Transplantation in the Treatment of B-Cell Non-Hodgkin Lymphoma.

    PubMed

    Shimoni, Avichai; Zwas, Shifra Tzila

    2016-03-01

    High-dose chemotherapy and autologous stem-cell transplantation (ASCT) is the standard therapy for patients with chemosensitive-relapsed or chemosensitive-refractory aggressive lymphoma. The use of rituximab, an anti-CD20 monoclonal antibody, has dramatically changed the outcome of patients with aggressive lymphoma, increasing both response and survival rates. However, despite this progress a significant proportion of patients are still refractory or relapse after frontline rituximab-containing therapy. Moreover, it is increasingly more difficult to rescue these patients with current salvage chemotherapy and ASCT approaches. Novel approaches are needed for these high-risk patients, especially in the rituximab era. Radioimmunotherapy (RIT) is a form of targeted therapy using the parent monoclonal antibody to deliver radiation emitted by a conjugated radioisotope, to the vicinity of antigen-positive tissues. Two radioimmunoconjugates--yttrium-90 ibritumomab tiuxetan (Zevalin) and iodine-131 tositumomab (Bexxar) have been in clinical use. There are multiple studies demonstrating the safety and efficacy of both agents in both indolent and aggressive lymphoma. Radiolabeled antibodies are ideal candidates to combine with high-dose chemotherapy and ASCT. RIT targets radiation to disease sites while limiting exposure of uninvolved critical organs, thus it can safely replace total-body irradiation during conditioning for ASCT. The major toxicity and limiting factor in RIT is myelotoxicity that is easily reversed by stem-cell rescue. RIT can be combined at standard doses with high-dose chemotherapy or can be given in escalated doses either alone or with high-dose chemotherapy before ASCT. Several phase II studies have shown the safety and potential efficacy of both agents using these approaches. A small randomized study comparing standard-dose Zevalin with combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) high-dose chemotherapy and BEAM alone suggested a

  17. Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome.

    PubMed

    Lunde, Sigrid; Kristoffersen, Einar K; Sapkota, Dipak; Risa, Kristin; Dahl, Olav; Bruland, Ove; Mella, Olav; Fluge, Øystein

    2016-01-01

    Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment. Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p = 0.011). There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab. A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up. Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab. Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p = 0.03). In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6-9.5 g/L, IgA 1.8-1.5 g/L, and IgM 0.97-0.70 g/L. Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B

  18. Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome

    PubMed Central

    Lunde, Sigrid; Kristoffersen, Einar K.; Sapkota, Dipak; Risa, Kristin; Dahl, Olav; Bruland, Ove; Mella, Olav; Fluge, Øystein

    2016-01-01

    Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment. Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p = 0.011). There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab. A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up. Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab. Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p = 0.03). In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6–9.5 g/L, IgA 1.8–1.5 g/L, and IgM 0.97–0.70 g/L. Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B

  19. The Effect of Combination Therapy with Rituximab and Intravenous Immunoglobulin on the Progression of Chronic Antibody Mediated Rejection in Renal Transplant Recipients

    PubMed Central

    Yun, Jintak; Khvan, Marina; Park, Cheol Whee; Choi, Yeong Jin; Kim, Yong-Soo; Yang, Chul Woo

    2014-01-01

    The treatment for chronic active antibody-mediated rejection (CAMR) remains controversial. We investigated the efficacy of rituximab (RTX) and intravenous immunoglobulin (IVIg) for CAMR. Eighteen patients with CAMR were treated with RTX (375 mg/m2) and IVIg (0.4 g/kg) for 4 days. The efficacy of RTX/IVIg combination therapy (RIT) was assessed by decline in estimated glomerular filtration rate per month (ΔeGFR) before and after RIT. Patients were divided into responder and nonresponder groups based on decrease and no decrease in ΔeGFR, respectively, and their clinical and histological characteristics were compared. Response rate to RIT was 66.7% (12/18), and overall ΔeGFR decreased significantly to 0.4 ± 1.7 mL·min−1·1.73 m−2 per month 6 months after RIT compared to that observed 6 months before RIT (1.8 ± 1.0, P < 0.05). Clinical and histological features between the 12 responders and the 6 nonresponders were not significantly different, but nonresponders had a significantly higher proteinuria levels at the time of RIT (2.5 ± 2.5 versus 7.0 ± 3.5 protein/creatinine (g/g), P < 0.001). The effect of the RIT on ΔeGFR had dissipated in all patients by 1 year post-RIT. Thus, RIT delayed CAMR progression, and baseline proteinuria level was a prognostic factor for response to RIT. PMID:24741626

  20. Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma

    PubMed Central

    Montraveta, Arnau; Xargay-Torrent, Sílvia; López-Guerra, Mónica; Rosich, Laia; Pérez-Galán, Patricia; Salaverria, Itziar; Beà, Silvia; Kalko, Susana G.; de Frias, Mercè; Campàs, Clara; Roué, Gaël; Colomer, Dolors

    2014-01-01

    Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses. The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients. PMID:24519895

  1. [Radioimmunotherapy with yttrium-90 ibritumomab tiuxetan. Clinical considerations, radiopharmacy, radiation protection, perspectives].

    PubMed

    Schomäcker, K; Dietlein, M; Schnell, R; Pinkert, J; Eschner, W; Zimmermanns, B; Fischer, T; Engert, A; Schicha, H

    2005-01-01

    90Y-ibritumomab tiuxetan (Zevalin) is currently approved for radioimmunotherapy of patients with relapsed or refractory follicular non-Hodgkin's lymphoma pretreated with rituximab. Future directions are the combined use of 90Y-ibritumomab tiuxetan as part of the initial treatment and as first-line multi-agent therapy of relapsed disease. Current studies investigate patients with other than follicular indolent histologies, e. g. diffuse large cell lymphoma. Labelling of 90Y ibritumomab tiuxetan is a safe procedure, the radiochemical purity is not disturbed by a higher room temperature or by metallic impurity. Quality control is recommended by thin layer chromatography (TLC), strips >15 cm are favourable. TLC cannot distinguish between the correctly radiolabelled antibodies and radiocolloid impurity. If necessary, additional HPLC should be performed. Radiocolloid impurities are absorbed to the solid phase and do not reach the eluate. If the radiochemical purity test is insufficient (<95%), the additional cleaning using EconoPac 10 DG columns (Biorad, Hercules, CA, USA) is a reliable procedure to reduce the percentage of free radionuclide. However, this procedure is not part of the approval. PMID:16163413

  2. Durable donor engraftment after radioimmunotherapy using α-emitter astatine-211–labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation

    PubMed Central

    Chen, Yun; Kornblit, Brian; Hamlin, Donald K.; Sale, George E.; Santos, Erlinda B.; Wilbur, D. Scott; Storer, Barry E.; Storb, Rainer

    2012-01-01

    To reduce toxicity associated with external γ-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the α-emitter, astatine-211 (211At), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 μCi/kg 211At-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with 211At doses less than or equal to 405 μCi/kg. Higher doses of 211At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 μCi/kg 211At-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/μL), lymphopenia (0-270 cells/μL), and thrombocytopenia (1500-6560 platelets/μL) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest 211At dose (155 μCi/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with 211At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning. PMID:22134165

  3. Durable donor engraftment after radioimmunotherapy using α-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation.

    PubMed

    Chen, Yun; Kornblit, Brian; Hamlin, Donald K; Sale, George E; Santos, Erlinda B; Wilbur, D Scott; Storer, Barry E; Storb, Rainer; Sandmaier, Brenda M

    2012-02-01

    To reduce toxicity associated with external γ-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the α-emitter, astatine-211 ((211)At), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 μCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with (211)At doses less than or equal to 405 μCi/kg. Higher doses of (211)At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 μCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/μL), lymphopenia (0-270 cells/μL), and thrombocytopenia (1500-6560 platelets/μL) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest (211)At dose (155 μCi/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with (211)At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning. PMID:22134165

  4. Anti-CD45 radioimmunotherapy using 211At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model

    SciTech Connect

    Orozco, Johnnie J.; Back, Tom; Kenoyer, Aimee L.; Balkin, Ethan R.; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Frayo, Shani; Hylarides, Mark; Green, Damian J.; Gopal, Ajay K.; Press, Oliver W.; Pagel, John M.

    2013-05-15

    Anti-CD45 Radioimmunotherapy using an Alpha-Emitting Radionuclide 211At Combined with Bone Marrow Transplantation Prolongs Survival in a Disseminated Murine Leukemia Model ABSTRACT Despite aggressive chemotherapy combined with hematopoietic cell transplant (HCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using antibodies (Ab) labeled primarily with beta-emitting radionuclides has been explored to reduce relapse.

  5. Improvement of Radioimmunotherapy Using Pretargeting

    PubMed Central

    Frampas, Eric; Rousseau, Caroline; Bodet-Milin, Caroline; Barbet, Jacques; Chatal, Jean-Francois; Kraeber-Bodéré, Françoise

    2013-01-01

    During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled monoclonal antibodies and receptor binding agents. Conventional radioimmunotherapy (RIT) is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor, and potential excessive radiation to normal tissues. Innovative approaches have been developed in order to enhance tumor absorbed dose while limiting toxicity to overcome the different limitations due to the tumor and host characteristics. Pretargeting techniques (pRIT) are a promising approach that consists of decoupling the delivery of a tumor monoclonal antibody (mAb) from the delivery of the radionuclide. This results in a much higher tumor-to-normal tissue ratio and is favorable for therapy as well and imaging. This includes various strategies based on avidin/streptavidin-biotin, DNA-complementary DNA, and bispecific antibody-hapten bindings. pRIT continuously evolves with the investigation of new molecular constructs and the development of radiochemistry. Pharmacokinetics improve dosimetry depending on the radionuclides used (alpha, beta, and Auger emitters) with prediction of tumor response and host toxicities. New constructs such as the Dock and Lock technology allow production of a variety of mABs directed against tumor-associated antigens. Survival benefit has already been shown in medullary thyroid carcinoma. Improvement in delivery of radioactivity to tumors with these pretargeting procedures associated with reduced hematologic toxicity will become the next generation of RIT. The following review addresses actual technical and clinical considerations and future development of pRIT. PMID:23802097

  6. Chemotherapy tolerance after radioimmunotherapy with 90Y-CC49 monoclonal antibody in patients with advanced non-small cell lung cancer: clinical effects and hematologic toxicity.

    PubMed

    Robert, Francisco; Busby, Elizabeth M; LoBuglio, Albert F

    2003-06-01

    The purpose of this retrospective analysis was to evaluate the hematologic toxicity and clinical outcome of salvage chemotherapy following (90)Y-CC49 radioimmunotherapy (RIT) in patients with non-small cell lung cancer (NSCLC). Sixteen patients from a total of 37 who were enrolled in a phase I trial of (90)Y-CC49 monoclonal therapy were treated with post-RIT salvage chemotherapy at our institution. Five patients had received chest radiation therapy prior to RIT, and seven patients had prior chemotherapy. The majority of these patients were treated with doses of (90)Y of >/= 14 mCi/m(2) (8-20 mCi/m(2)), and four of them received concurrent 96-hour taxol infusion. The maximum tolerated dose of this study was exceeded at 17 mCi/m(2), and grade 4 thrombocytopenia/neutropenia were the dose-limiting toxicities. Twelve patients received one chemotherapy regimen as salvage therapy, and four patients had more than one regimen. Four patients (25%) experienced reversible grade 4 neutropenia, but no grade 4 thrombocytopenia was observed. Five patients had stable disease. The median survival from start of salvage therapy was 5.5 months. Our data suggest that therapy with RIT did not significantly affect survival of these patients. Taking into consideration the potential clinical relevance of integration of RIT with other treatment modalities, it is important to expand this clinical experience in order to support combined modality strategies. PMID:12954119

  7. Rituximab use in adult primary glomerulopathy: where is the evidence?

    PubMed Central

    Mallat, Samir G; Itani, Houssam S; Abou-Mrad, Rana M; Abou Arkoub, Rima; Tanios, Bassem Y

    2016-01-01

    Rituximab is a chimeric anti-CD20 antibody that results in depletion of B-cell lymphocytes. It is currently used in the treatment of a variety of autoimmune diseases, in addition to CD20-positive lymphomas. The use of rituximab in the treatment of the adult primary glomerular diseases has emerged recently, although not yet established as first-line therapy in international guidelines. In patients with steroid-dependent minimal change disease or frequently relapsing disease, and in patients with idiopathic membranous nephropathy (IMN), several retrospective and prospective studies support the use of rituximab to induce remission, whereas in idiopathic focal and segmental glomerulosclerosis (FSGS), the use of rituximab has resulted in variable results. Evidence is still lacking for the use of rituximab in patients with immunoglobulin A nephropathy (IgAN) and idiopathic membranoproliferative glomerulonephritis (MPGN), as only few reports used rituximab in these two entities. Randomized controlled trials (RCTs) are warranted and clearly needed to establish the definitive role of rituximab in the management of steroid-dependent and frequently relapsing minimal change disease, IMN, both as first-line and second-line treatment, and in MPGN. We await the results of an ongoing RCT of rituximab use in IgAN. Although current evidence for the use of rituximab in patients with idiopathic FSGS is poor, more RCTs are needed to clarify its role, if any, in the management of steroid-resistant or steroid-dependent FSGS. PMID:27621641

  8. Radioimmunotherapy of micrometastases: Theoretical evaluation of adjuvant treatment

    SciTech Connect

    Sgouros, G.; Yorke, E.D.; Willins, J.D.

    1994-05-01

    Failure of current cancer treatment modalities is generally associated with the inability to control distant metastatic disease. This work examines the adjuvant use of radiolabeled antibodies for targeting micrometastases. A Monte Carlo program is used to estimate the number and size distribution of metastases that are present in a given (node-negative) prostate cancer patient population at the time of diagnosis. These results are used in a second program that solves the equations associated with antibody (Ab) diffusion, binding, and dissociation to yield the kinetics of Ab penetration within pre-vascularized micrometastases. These simulated kinetic data are then micrometastasis. Using a two-compartment macroscopic model of Ab distribution, the red marrow dose is also calculated. Calculations are performed for I-123 and for I-131-labeled antibody. With these results, the fraction of the patient population that would benefit from radioimmunotherapy is estimated. The analysis suggests that a single administration of radioimmunotherapy following surgery or external beam radiotherapy will yield a potentially lethal dose ({ge} 20 Gy for I-123 and {ge} 38 Gy for I-131) to 23% of micrometastases present at the time of initial diagnosis without inducing prohibitive red marrow morbidity (absorbed dose {le}2.5 Gy). Multiple courses of radioimmunotherapy, designed to target micrometastases that are initially too small but that eventually reach a targetable size (i.e., 20 {mu}m {le} micromet. radius {le}200{mu}m), will yield a potentially lethal results suggest that approximately 25% of high risk prostate cancer patients (i.e., patients with occult metastases at the time of diagnosis) could benefit from single course of radioimmunotherapy; multiple courses of radioimmunotherapy could benefit 75% of high risk prostate cancer patients.

  9. Improved radioimmunotherapy of hematologic malignancies. [Final report

    SciTech Connect

    Press, O.W.

    1992-03-24

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides ({sup 131}Iodine, {sup 111}Indium, {sup 90}Yttrium, {sup 99m}Technetium, {sup 186}Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer.

  10. Acute Respiratory Distress Syndrome and Posterior Reversible Encephalopathy Syndrome following Rituximab Therapy.

    PubMed

    Wardrope, Katrina E; Manson, Lynn; Metcalfe, Wendy; Sullivan, Eoin D O

    2016-01-01

    The anti-CD20 monoclonal antibody rituximab is associated with rare but significant adverse events, notably posterior reversible encephalopathy syndrome (PRES) and acute respiratory distress syndrome (ARDS). We report a case of concomitant ARDS and PRES developing after rituximab therapy for treatment of cryoglobulinaemic vasculitis. There are 7 reported cases of PRES complicating rituximab use. PRES onset varied from immediate to 21 days after administration. All patients recovered completely, and rituximab was reintroduced in half of the cases. The occurrence of ARDS in association with rituximab is rarer. Only 3 confirmed cases exist, and ARDS may occur as a delayed reaction. PMID:27275457

  11. Acute Respiratory Distress Syndrome and Posterior Reversible Encephalopathy Syndrome following Rituximab Therapy

    PubMed Central

    Wardrope, Katrina E.; Manson, Lynn; Metcalfe, Wendy; Sullivan, Eoin D. O

    2016-01-01

    The anti-CD20 monoclonal antibody rituximab is associated with rare but significant adverse events, notably posterior reversible encephalopathy syndrome (PRES) and acute respiratory distress syndrome (ARDS). We report a case of concomitant ARDS and PRES developing after rituximab therapy for treatment of cryoglobulinaemic vasculitis. There are 7 reported cases of PRES complicating rituximab use. PRES onset varied from immediate to 21 days after administration. All patients recovered completely, and rituximab was reintroduced in half of the cases. The occurrence of ARDS in association with rituximab is rarer. Only 3 confirmed cases exist, and ARDS may occur as a delayed reaction.

  12. The spectrum of use of rituximab in chronic lymphocytic leukemia

    PubMed Central

    Tedeschi, Alessandra; Vismara, Eleonora; Ricci, Francesca; Morra, Enrica; Montillo, Marco

    2010-01-01

    The monoclonal chimeric anti-CD20 antibody, rituximab, has considerably improved therapeutic outcome in B-cell chronic lymphocytic leukemia. Rituximab has limited clinical activity when used as a single agent. The combination of the monoclonal antibody with fludarabine-based regimens clearly demonstrated, in Phase II and randomized trials, an increase in clinical efficacy in previously untreated and pretreated patients. Furthermore the addition of rituximab enabled the eradication of minimal residual disease, which is correlated with the prognosis in a high proportion of patients. Although the combination of rituximab with fludarabine-based regimens increased myelosuppression and immunosuppression, incidence of infections did not increase. The benefit of adding rituximab to other purine analogs or other chemotherapeutic combination regimens has also been explored. Moreover there could be a role for achieving better quality of responses with the combination of different monoclonal antibodies, considering that they target different antigens and exert different mechanism of action. Although the role of rituximab as maintenance therapy in low grade non-Hodgkin’s lymphomas has been determined, the benefit and optimal schedule in chronic lymphocytic leukemia are still under investigation. This review brings together knowledge of the pharmacokinetics, mechanism of action and clinical use of rituximab in chronic lymphocytic leukemia. PMID:21289858

  13. Rituximab in immunologic glomerular diseases

    PubMed Central

    Ejaz, A Ahsan; Asmar, Abdo; Alsabbagh, Mourad M

    2012-01-01

    Experimental data suggest that the B-cell antigen CD20 may play a significant role in the pathogenesis of many diseases including glomerular diseases. These and other findings underpin the central concept of B-cell-depleting therapies that target CD20 antigen as treatments for lupus nephritis, idiopathic membranous nephropathy, focal segmental glomerulosclerosis, cryglobulinemic glomerulonephritis, antibody mediated renal allograft rejection and recurrent glomerulonephritis in renal allograft. Use of rituximab as a B-cell depleting therapy has been associated with clinical improvement and has emerged as a possible adjunct or alternative treatment option in this field of nephrology. PMID:22377738

  14. Rituximab and chemotherapy in diffuse large B-cell lymphoma.

    PubMed

    Sonet, Anne; Bosly, André

    2009-06-01

    Rituximab is an anti-CD20 chimeric monoclonal antibody with activity in nearly all subtypes of B-cell lymphomas. Association of rituximab with chemotherapy (mostly the cyclophosphamide, doxorubicin, vincristine and prednisolone [CHOP] regimen) in diffuse large B-cell lymphoma (DLBCL) represents an extraordinary revolution in the prognosis of DLBCL, and is the new standard of therapy in elderly and young, low-risk patients. Despite the lack of randomized, clinical trials in younger patients with high risk, rituximab is also a standard of care in these patients in clinical practice, at least in North America. The practice is based on observational trials (e.g., the British Columbia Registry) and the missing logic in classifying patients as 'younger' or 'older': 60 years old or 65 years old. In Europe, trials are ongoing to establish the best treatment for young, high-risk patients. Association of rituximab and chemotherapy deeply modifies prognostic factors defined before the rituximab era. PMID:19496708

  15. [Recurrent infections in an ITP patient treated with rituximab].

    PubMed

    Rosenberg-Bezalel, Shira; Asher, Ilan; Sthoeger, Zev

    2012-11-01

    Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by hypogammaglobulinemia and recurrent infections. Various mechanisms have been implied in the disease pathophysiology. Patients with CVID are at increased risk of developing ITP (Immune Thrombocytopenia Purpura) and/ or AIHA (Autoimmune Haemolytic Anemia). Rituximab, a humanized anti-CD20 monoclonal antibody, is increasingly being used for autoimmune cytopenias including ITP and AIHA. This is a case history of a patient treated with Rituximab due to refractory ITP. A year after completion of therapy the patient started suffering from an increased frequency of infections. Six years after treatment with Rituximab the patient was diagnosed with CVID and IVIG replacement treatment was started. The main possibilities that this patient presents include aggravation of CVID, first presented as ITP, after Rituximab treatment versus CVID secondary to Rituximab treatment. PMID:23367730

  16. Role of Rituximab and Rituximab Biosimilars in Diffuse Large B-Cell Lymphoma.

    PubMed

    Coleman, Morton; Lammers, Philip E; Ciceri, Fabio; Jacobs, Ira A

    2016-04-01

    Diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma (NHL), is the most-common subtype of NHL. DLBCL can be classified into at least 3 major immunologically distinct types, which contributes to considerable variation in disease prognosis and response to treatment. DLBCL potentially is curable, even when diagnosed at advanced stages. The current standard of care for most patients with untreated or relapsed/refractory DLBCL is chemoimmunotherapy containing rituximab, an anti-CD20 monoclonal antibody. With advanced understanding of the molecular mechanisms involved in the pathogenesis of DLBCL and specific signaling pathways that are activated in different subtypes, potential new therapeutic targets have been identified, some of which are at the late stages of clinical development. This review summarizes the critical role of rituximab in the current standard of care treatment for DLBCL and discusses why rituximab is likely to remain an important component of treatment options for DLBCL in the foreseeable future. In addition, current and emerging therapeutic agents, including potential benefits of rituximab biosimilars, for patients with DLBCL are discussed. The advent of rituximab biosimilars may facilitate accessibility of rituximab-based chemotherapies to patients with DLBCL and has potential cost-saving benefits for healthcare systems globally. PMID:26906106

  17. Acquired Hemophilia A Successfully Treated with Rituximab

    PubMed Central

    D’Arena, Giovanni; Grandone, Elvira; Di Minno, Matteo Nicola Dario; Musto, Pellegrino; Di Minno, Giovanni

    2015-01-01

    Acquired hemophilia A (AHA) is a rare bleeding disorder due to the development of specific autoantibodies against factor VIII. The anti-CD20 monoclonal antibody Rituximab has been proven to be effective in obtaining a long-term suppression of inhibitors of AHA, besides other immunosuppressive standard treatments. Here we describe a case of idiopathic AHA in a 60-year old man successfully treated with rituximab. He showed a complete clinical response with a normalization of clotting parameters after 5 weekly courses of rituximab given at a dose of 375 mg/sqm., but after stopping rituximab, an initial worsening of coagulation parameters induced the addition of 3 further courses. At present, the patient is in complete clinical and hematological remission after 200 days. This case confirms that Rituximab may be a safe and useful tool to treat AHA and, a prolonged administration can overcome the initial resistance. However, the precise position of this drug in the therapeutic strategy (first or second-line, alone or in combination with other drugs) remains to be established and warrants further investigation. PMID:25745551

  18. Efficient one-step radiolabeling of monoclonal antibodies to high specific activity with Actinium-225 for alpha-particle radioimmunotherapy of cancer

    PubMed Central

    Maguire, William F.; McDevitt, Michael R.; Smith-Jones, Peter M.; Scheinberg, David A.

    2015-01-01

    Targeted alpha-particle radiation using the radioisotope 225Actinium (225Ac) is a promising form of therapy for various types of cancer. Historical obstacles to the use of 225Ac have been the difficulty in finding suitable chelators to stably attach it to targeting vehicles such as peptides and monoclonal antibodies, the low specific activities of the products, and the lack of cost-effective radiolabeling procedures. We initially solved the first problem with a procedure involving two chemical steps that has been used as a standard in preclinical and clinical studies. However, this procedure involves the loss of 90% of the input 225Ac. A more efficient, economical process is needed to facilitate the more widespread use of 225Ac. Methods We conjugated representative antibodies with two forms of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), as well as other chelators as controls. We developed conditions to radiolabel these constructs in one chemical step and characterized their stability, immunoreactivity, biodistribution, and therapeutic efficacy in healthy and tumor-bearing mice. Results DOTA- antibody constructs were labeled to a wide range of specific activities in one chemical step at 37 °C. Radiochemical yields were approximately 10-fold higher and specific activities were up to 30-fold higher than with the previous approach. The products retained immunoreactivity and were stable to serum challenge in vitro and in mice. Labeling kinetics of DOTA- antibody constructs linked through a benzyl isothiocyanate linkage were more favorable than those linked through a N-hydroxysuccinimide linkage. Tissue distribution was similar but not identical between the constructs. The constructs produced specific therapeutic responses in a mouse model of acute myeloid leukemia. Conclusion We have characterized an efficient, one-step radiolabeling method that produces stable, therapeutically active conjugates of antibodies with 225Ac at high specific activity

  19. Rituximab Desensitization in Pediatric Patients: Results of a Case Series

    PubMed Central

    Lee, Joyce P.; Platt, Craig D.

    2016-01-01

    Rituximab is a monoclonal antibody (mAb) primarily used to treat oncologic and autoinflammatory conditions. Although hypersensitivity reactions (HSRs) and desensitization protocols to mAbs have been well described in adults, the experience in the pediatric population is very limited. We sought to determine the safety and efficacy of desensitization to rituximab in the pediatric population at our institution. We retrospectively reviewed the experience with HSRs and desensitization to rituximab during a 5-year period in our tertiary care pediatric center, including reaction evaluation, premedication regimens, and desensitization procedures and protocols. A total of 17 desensitizations to rituximab were performed in three patients. A 14-year-old patient underwent successful desensitization to rituximab using a published adult protocol without incident. Two younger patients (ages 7 years and 23 months) experienced significant reactions during initial desensitization attempts. Therefore, we designed a modified desensitization protocol to rituximab, with particular attention to the rate of infusion as mg/kg/h. This new patient weight-based protocol was successfully used in a total of 13 desensitizations in these two patients. Desensitization to rituximab was a safe and effective procedure in our pediatric population. We present a new patient weight-based desensitization protocol for pediatric patients who develop HSRs to rituximab, with particular usefulness for younger pediatric patients and potential utility in pediatric patients with HSRs to other mAbs.

  20. Safety and Clinical Activity of a Combination Therapy Comprising Two Antibody-Based Targeting Agents for the Treatment of Non-Hodgkin Lymphoma: Results of a Phase I/II Study Evaluating the Immunoconjugate Inotuzumab Ozogamicin With Rituximab

    PubMed Central

    Fayad, Luis; Offner, Fritz; Smith, Mitchell R.; Verhoef, Gregor; Johnson, Peter; Kaufman, Jonathan L.; Rohatiner, Ama; Advani, Anjali; Foran, James; Hess, Georg; Coiffier, Bertrand; Czuczman, Myron; Giné, Eva; Durrant, Simon; Kneissl, Michelle; Luu, Kenneth T.; Hua, Steven Y.; Boni, Joseph; Vandendries, Erik; Dang, Nam H.

    2013-01-01

    Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20+/CD22+ B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. Results In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m2) was confirmed to be the same as that for single-agent INO (1.8 mg/m2). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL. Conclusion R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20+/CD22+ B-cell NHL. PMID:23295790

  1. Prolonged Remission in Neuromyelitis Optica Following Cessation of Rituximab Treatment.

    PubMed

    Weinfurtner, Kelley; Graves, Jennifer; Ness, Jayne; Krupp, Lauren; Milazzo, Maria; Waubant, Emmanuelle

    2015-09-01

    Neuromyelitis optica is an autoimmune disease characterized by acute episodes of transverse myelitis and optic neuritis. Several small, open-label studies suggest rituximab, a monoclonal antibody against CD20, prevents relapses in neuromyelitis optica; however, there is little consensus on timing or duration of treatment. Here we report four patients with severe relapsing neuromyelitis optica who were stabilized on rituximab and, after discontinuing treatment, continued to experience prolonged remission of their disease. Remission ranged from 4.5 to 10.5 years total, including 3 to 9 years off all therapies. The patients had sustained clinical responses despite normal B-lymphocyte levels and, in at least 2 patients, continued seropositivity for aquaporin-4 antibodies. These cases suggest that rituximab may induce prolonged remission in certain neuromyelitis optica patients, and they highlight the need for further elucidation of rituximab's mechanism in neuromyelitis optica. PMID:25387545

  2. Rituximab for the treatment of rheumatoid arthritis: an update

    PubMed Central

    Mok, Chi Chiu

    2014-01-01

    Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule expressed on the surface of B cells. It was first used in the treatment of non-Hodgkin’s lymphoma and later approved for the treatment of rheumatoid arthritis (RA) that does not respond adequately to disease-modifying antirheumatic drugs, including the anti-tumor-necrosis-factor (TNF) biologics. Sustained efficacy in RA can be achieved by repeated courses of rituximab. However, the optimal dose and retreatment schedule of rituximab in RA remains to be established. Seropositivity, complete B cell depletion shortly after treatment, and previous failure to no more than one anti-TNF agent are three factors associated with greater clinical benefits to rituximab. Infusion reaction to the first dose of rituximab occurs in approximately 25% of RA patients, and the incidence reduces with subsequent exposure. Immunogenicity to the chimeric compound occurs in 11% of RA patients, but this does not correlate with its efficacy in B cell depletion. Extended observation of randomized controlled trials in RA does not reveal a significant increase in the incidence of serious infections related to rituximab compared to placebo groups, and the infection rate remains static over time. Repeated treatment with rituximab is associated with hypogammaglobulinemia, which may increase the risk of serious, but rarely opportunistic, infections. Reactivation of occult hepatitis B infection has been reported in RA patients receiving rituximab, but no increase in the incidence of tuberculosis was observed. Screening for baseline serum immunoglobulin G level and hepatitis B status (including occult infection) is important, especially in Asian countries where hepatitis B infection is prevalent. The rare but fatal progressive multifocal leukoencephalopathy linked to the use of rituximab has to be noted. Postmarketing surveillance and registry data, particularly in Asia, are necessary to establish the long-term efficacy and

  3. Objective cerebrospinal fluid response to intraventricular rituximab in indolent CNS lymphoma

    PubMed Central

    Strowd, Roy E; Abuali, Inas A; Grossman, Stuart A

    2016-01-01

    SUMMARY Indolent CNS lymphomas (CNSLs) are rare and no guidelines exist for management. Recent literature highlights the potential for safe and tolerable intrathecal (IT) delivery of rituximab, a large anti-CD20 monoclonal antibody, for aggressive CNSL. We report a patient with relapsed indolent CNSL who failed systemic rituximab and could not tolerate IT chemotherapies, but had an objective response of 6 months duration to IT rituximab. PMID:25905905

  4. Radioimmunotherapy: Development of an effective approach

    SciTech Connect

    Not Available

    1987-01-01

    Goals of this program are to answer the fundamental scientific questions for the development of an effective approach for delivering radiation therapy to cancer on antibody-based radiopharmaceuticals. The following list consists of highlights of developments from our program: documented therapeutic response of lymphoma in patients receiving radioimmunotherapy; development and application of quantitative radionuclide imaging techniques for therapy planning and dosimetry calculations; multicompartmental modeling and analysis of the in vivo MoAb kinetics in patients; a MoAb macrocycle chelate for Cu-67: development, production, in vitro and in vivo testing; NMR analysis of immunoradiotherapeutic effects on the metabolism of lymphoma; analysis of the variable molecular characteristics of the MoAb radiopharmaceutical, and their significance; in vivo studies in mice and patients of the metabolism of radioiodinated MoAb as well as In-111 CITC MoAb; and biodistribution of Cu-67 TETA MoAb in nude mice with human lymphoma.

  5. Pretargeted Radioimmunotherapy for Hematologic and Other Malignancies

    PubMed Central

    Press, Oliver W.; Pagel, John M.

    2010-01-01

    Summation Radioimmunotherapy (RIT) has emerged as one of the most promising treatment options, particularly for hematologic malignancies. However, this approach has generally been limited by a suboptimal therapeutic index (target-to-nontarget ratio) and an inability to deliver sufficient radiation doses to tumors selectively. Pretargeted RIT (PRIT) circumvents these limitations by separating the targeting vehicle from the subsequently administered therapeutic radioisotope, which binds to the tumor-localized antibody or is quickly excreted if unbound. A growing number of preclinical proof-of-principle studies demonstrate that PRIT is feasible and safe and provides improved directed radionuclide delivery to malignant cells compared with conventional RIT while sparing normal cells from nonspecific radiotoxicity. Early phase clinical studies corroborate these preclinical findings and suggest better efficacy and lesser toxicities in patients with hematologic and other malignancies. With continued research, PRIT-based treatment strategies promise to become cornerstones to improved outcomes for cancer patients despite their complexities. PMID:20423225

  6. Radioimmunotherapy for Waldenstrom's macroglobulinemia.

    PubMed

    Emmanouilides, Christos

    2003-04-01

    Radioimmunotherapy targeting CD20 is a promising novel treatment for lymphoma. Prior trials have established the safe dose of Zevalin ((90)Y-ibritumomab tiuxetan; IDEC Pharmaceuticals) for patients with no more than 25% bone marrow (BM) involvement. Zevalin is expected to be an effective treatment for WM; however, the safe dose has not been defined. A phase I clinical trial has been designed to define the maximum-tolerated dose (MTD) of Zevalin in patients with WM and BM involvement up to 50%. Eligible patients need to have adequate hematologic indices (absolute neutrophil count [ANC] > 1,500/microL, platelets > 100,000/microL). The starting dose of (90)Y-Zevalin is 0.08 mCi/kg. Dose escalation by 0.04 mCi/kg in cohorts of three to six patients will be performed. Patients will be re-treated at 12 weeks if there is no complete response, no progression, and no dose-limiting toxicity. If the degree of BM involvement remains in the 20% to 50% range, re-treatment will involve a similar dose of Zevalin; if it is <20%, patients will receive Zevalin to the maximum allowed cumulative dose of 0.4 mCi/kg (or 0.3 mCi/kg for mild thrombocytopenia). Despite the phase I design, the re-treatment provision is expected to result in significant clinical benefit. PMID:12720148

  7. Radioimmunotherapy of Solid Tumors: Searching for the Right Target

    PubMed Central

    Song, Hong; Sgouros, George

    2015-01-01

    Radioimmunotherapy of solid tumors remains a challenge despite the tremendous success of 90Y ibritumomab tiuxetan (Zevalin) and 131I Tositumomab (Bexxar) in treating non-Hodgkin’s lymphoma. For a variety of reasons, clinical trials of radiolabeled antibodies against solid tumors have not led to responses equivalent to those seen against lymphoma. In contrast, promising responses have been observed with unlabeled antibodies that target solid tumor receptors associated with cellular signaling pathways. These observations suggest that anti-tumor efficacy of the carrier antibody might be critical to achieving clinical responses. Here, we review and compare tumor antigens targeted by radiolabeled antibodies and unlabeled antibodies used in immunotherapy. The review shows that the trend for radiolabeled antibodies under pre-clinical development is to also target antigens associated with signaling pathways that are essential for the growth and survival of the tumor. PMID:21034423

  8. The Effect of Rituximab on Vaccine Responses in Patients with Immune Thrombocytopenia

    PubMed Central

    Nazi, Ishac; Kelton, John G.; Larché, Mark; Snider, Denis P.; Heddle, Nancy M.; Crowther, Mark A.; Cook, Richard J.; Tinmouth, Alan T.; Mangel, Joy; Arnold, Donald M.

    2013-01-01

    B-cell depletion therapy may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). Capitalizing on a multicenter randomized placebo-controlled trial, we investigated the effects of rituximab on the antibody and cellular responses to Streptococcus pneumoniae polysaccharide vaccine and Haemophilus influenzae type b (Hib) conjugate vaccine in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n=17) or placebo (n=7). Among 20 evaluable patients, 3/14 (21%) in the rituximab group and 4/6 (67%) in the placebo group achieved a 4-fold increase in anti-pneumococcal antibodies (p=0.12). For anti-Hib antibodies, 4/14 (29%) and 5/6 (83%), respectively, achieved a 4-fold increase (p<0.05). Fewer patients in the rituximab group demonstrated functional Hib killing (2/14 [14%] versus 5/6 [83%], p<0.05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, pre-plasma cell blasts and interferon-γ secreting T-cells were reduced in rituximab-treated patients. We found that antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with the depleted B-cell pool. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in patients with ITP. PMID:23851398

  9. Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts

    PubMed Central

    DeNardo, Sally J.; Kukis, David L.; Kroger, Linda A.; O’Donnell, Robert T.; Lamborn, Kathleen R.; Miers, Laird A.; DeNardo, David G.; Meares, Claude F.; DeNardo, Gerald L.

    1997-01-01

    Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. 90Y-labeled DOTA-peptide-ChL6 (90Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N",N‴-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and 90Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving 90Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24–72 hours before 90Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after 90Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with 90Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to 90Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with 90Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with 90Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy. PMID:9108094

  10. Two cases of refractory Wegener's granulomatosis successfully treated with rituximab.

    PubMed

    Tamura, Naoto; Matsudaira, Ran; Hirashima, Mika; Ikeda, Makoto; Tajima, Michiko; Nawata, Masuyuki; Morimoto, Shinji; Kaneda, Kazuhiko; Kobayashi, Shigeto; Hashimoto, Hiroshi; Takasaki, Yoshinari

    2007-01-01

    Conventional therapy for Wegener's granulomatosis, steroid and cyclophosphamide, fails to control disease activity in some refractory patients and has treatment-related toxicity. B cell depletion therapy using rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be effective for certain autoimmune diseases including antineutrophil cytoplasmic antibody (ANCA) -associated systemic vasculitis. We report two refractory cases of Wegener's granulomatosis: one with bronchial and pulmonary involvement and retroorbital granuloma, the other with retroorbital granuloma and hypertrophic pachymeningitis causing severe headache. Rituximab was effective in both cases, with diminished granuloma and reduced ANCA titers, allowing steroids to be tapered. No adverse effects were detected. PMID:17409608

  11. Dosimetry and quantitative radionuclide imaging in radioimmunotherapy: Final report, July 15, 1992-July 14, 1996

    SciTech Connect

    Leichner, P.K.

    1996-09-01

    Brief summaries of the principal accomplishments of this project on the development of quantitative SPECT for high energy photons (87Y, 19F) and stability testing of 87Y-labeled antibodies in the nude mouse model, development of an unified approach to photon and beta particle dosimetry, quantitative SPECT for nonuniform attenuation, and development of patient-specific dosimetry in radioimmunotherapy.

  12. Stiff-person syndrome treated with rituximab

    PubMed Central

    Lobo, Marcelo Evangelista; Araújo, Marx Lincoln Barros; Tomaz, Carlos Alberto Bezerra; Allam, Nasser

    2010-01-01

    Stiff-person syndrome (SPS) is a rare neurological condition consisting of progressive and fluctuating rigidity of the axial muscles combined with painful spasms. The pathophysiology of SPS is not fully understood, but there seems to be an autoimmune component. The use of rituximab, a chimeric monoclonal antibody targeting CD20 protein in the surface of mature B cells, for the treatment of SPS is a recent therapeutical approach showing promising results. The authors present a case report of a 41-year-old female patient diagnosed with SPS who was treated with rituximab in a public hospital in Brasília, Brazil, showing a good and safe response to the treatment so far. Our data go along with some recent articles published in the literature. PMID:22802263

  13. Rituximab efficiently depletes B cells in lung tumors and normal lung tissue

    PubMed Central

    Joly-Battaglini, Albane; Hammarström, Clara; Stankovic, Branislava; Aamodt, Henrik; Stjärne, Johan; Brustugun, Odd Terje; Helland, Åslaug; Øynebråten, Inger; Corthay, Alexandre

    2016-01-01

    Rituximab is a monoclonal antibody that targets the CD20 B-cell-specific antigen and is widely used as therapy for B-cell lymphoma. Since rituximab depletes both malignant and normal B cells, it is increasingly being used to treat various conditions in which normal B cells have a pathogenic role, such as rheumatoid arthritis and multiple sclerosis. It is well-established that rituximab efficiently eliminates B cells in blood, lymph nodes, and spleen. In contrast, the effect of rituximab in non-lymphoid tissues remains poorly documented and is debated. Here, we report a rheumatoid arthritis patient who was treated with rituximab before receiving thoracic surgery for non-small cell lung cancer. Using flow cytometry and immunohistochemistry, we show that rituximab efficiently depleted CD20-positive B cells in a primary lung tumor, in lung-associated lymph nodes, and in normal lung tissue. We conclude that rituximab may be very efficient at depleting normal B cells in the lungs. This property of rituximab may potentially be exploited for the treatment of conditions in which pathogenic B cells reside in the lungs. On the other hand, the clearance of lung B cells may provide an explanation for the rare cases of severe non-infectious pulmonary toxicity of rituximab. PMID:27081474

  14. Radioimmunotherapy: Development of an effective approach

    SciTech Connect

    DeNardo, S.J.

    1991-01-01

    We plan to extend our success in treating B cell malignancies with {sup 131}I labeled Lym-1 by a major effort in therapy with {sup 67}Cu Lym-1. Yttrium-90 labeled by a macrocycle, DOTA will be studied in patients as a continuation of the {sup 111}In-BAD (DOTA) Lym-1 studies. Excellent images and pharmacokinetics of the {sup 111}In-BAD(DOTA)-Lym-1 studies. Lymphomas and related diseases represent a special case for radioimmunotherapy because of their documented radiosensitivity and immunodeficiency, and thus offer a unique opportunity to conduct therapeutic feasibility studies in a responsive human model. Using marine and chimeric L6 and other MoAb to breast cancer, we have applied the strategies that were developed in taking Lym-1 antibody from the bench to the patient. We have examined a number of monoclonal antibodies for treatment of breast cancer and chose chimeric L6 for prototype studies because of certain characteristics. The chemistry of attachment of conjugates to antibodies and their impact on immunological targeting biological activities (cytotoxicity), metabolic fate, and therapeutic index will continue to be a major strength and function of this program. This grant has supported the conception, synthesis, and development of the first macrocylic, bifunctional chelating agent TETA (6-p-nitrobenzyl-1,4,8,11-tetraazatetradecane-N,N{prime},N{double prime}, N{prime}{double prime}-tetraacetic acid and its derivatives, including Lym-1-2IT-BAT), for use in Cu-67-based radioimmunodiagnosis and therapy. This work has led to the further development of several new macrocylic bifunctional chelating agents for copper, indium, yttrium and other metals. In addition, successful Cu-67 labelings of Lym-1-2IT-BAT for human radiopharmaceutical have shown patient pharmacokinetics of {sup 67}Cu-BAT(TETA)-Lym-1 with promising therapeutic dosimetry.

  15. Rituximab for treatment of inhibitors in haemophilia A. A Phase II study.

    PubMed

    Leissinger, C; Josephson, C D; Granger, S; Konkle, B A; Kruse-Jarres, R; Ragni, M V; Journeycake, J M; Valentino, L; Key, N S; Gill, J C; McCrae, K R; Neufeld, E J; Manno, C; Raffini, L; Saxena, K; Torres, M; Marder, V; Bennett, C M; Assmann, S F

    2014-09-01

    The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m² weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5-10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies. PMID:24919980

  16. Radioimmunotherapy for Treatment of Acute Leukemia.

    PubMed

    Bodet-Milin, Caroline; Kraeber-Bodéré, Françoise; Eugène, Thomas; Guérard, François; Gaschet, Joëlle; Bailly, Clément; Mougin, Marie; Bourgeois, Mickaël; Faivre-Chauvet, Alain; Chérel, Michel; Chevallier, Patrice

    2016-03-01

    Acute leukemias are characterized by accumulation of immature cells (blasts) and reduced production of healthy hematopoietic elements. According to the lineage origin, two major leukemias can be distinguished: acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Although the survival rate for pediatric ALL is close to 90%, half of the young adults with AML or ALL and approximately 90% of older patients with AML or ALL still die of their disease, raising the need for innovative therapeutic approaches. As almost all leukemic blasts express specific surface antigens, targeted immunotherapy appears to be particularly promising. However, published results of immunotherapy alone are generally modest. Radioimmunotherapy (RIT) brings additional therapeutic mechanisms using radiolabeled monoclonal antibodies (mAbs) directed to tumor antigens, thus adding radiobiological cytotoxicity to immunologic cytotoxicity. Because of the high radiosensitivity of tumor cells and the diffuse widespread nature of the disease, making it rapidly accessible to circulating radiolabeled mAbs, acute leukemias represent relevant indications for RIT. With the development of recombinant and humanized mAbs, innovative radionuclides, and more efficient radiolabeling and pretargeting techniques, RIT has significantly improved over the last 10 years. Different approaches of α and β RIT targeting CD22, CD33, CD45, or CD66 antigens have already been evaluated or are currently being developed in the treatment of acute leukemia. This review summarizes the preclinical and clinical studies demonstrating the potential of RIT in treatment of AML and ALL. PMID:26897718

  17. Radionuclides for radioimmunotherapy: criteria for selection.

    PubMed

    Geerlings, M W

    1993-01-01

    In developing and designing radioimmunotherapy, the selection of the isotope is a major factor. This selection depends on a number of criteria and parameters, affecting usefulness and feasibility. Usefulness is directly related to the radiological performance of the ionising radiation in relation to tissue and its morphology, with a major distinction between the effects of alpha and beta-particles (or rays). Usefulness is also directly related to the pharmacodynamic performance of the isotope-carrier (e.g. antibody) complex, where the proper choice of isotope radiodecay halflife is of major importance. Feasibility depends on availability of the components in the isotope-ligand-carrier complex, and also on convenience and safety aspects in the preparation and the handling of the materials as well as in their application in patients. A comparison is made between the various properties of alpha-emitting isotopes that have been proposed over a number of years, concluding that the combination 225Ac- 213Bi deserves serious further attention. PMID:8277210

  18. Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis

    PubMed Central

    Stone, John H.; Merkel, Peter A.; Spiera, Robert; Seo, Philip; Langford, Carol A.; Hoffman, Gary S.; Kallenberg, Cees G.M.; St. Clair, E. William; Turkiewicz, Anthony; Tchao, Nadia K.; Webber, Lisa; Ding, Linna; Sejismundo, Lourdes P.; Mieras, Kathleen; Weitzenkamp, David; Ikle, David; Seyfert-Margolis, Vicki; Mueller, Mark; Brunetta, Paul; Allen, Nancy B.; Fervenza, Fernando C.; Geetha, Duvuru; Keogh, Karina A.; Kissin, Eugene Y.; Monach, Paul A.; Peikert, Tobias; Stegeman, Coen; Ytterberg, Steven R.; Specks, Ulrich

    2011-01-01

    BACKGROUND Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; Clinical

  19. An overview of imaging techniques and physical aspects of treatment planning in radioimmunotherapy

    SciTech Connect

    Leichner, P.K. ); Koral, K.F. ); Jaszczak, R.J. ); Green, A.J. ); Chen, G.T.Y.; Roeske, J.C. )

    1993-03-01

    Planar and tomographic imaging techniques and methods of treatment planning in clinical radioimmunotherapy are reviewed. In clinical trials, the data needed for dosimetry and treatment planning are, in most cases, obtained from noninvasive imaging procedures. The required data include tumor and normal organ volumes, the activity of radiolabeled antibodies taken up in these volumes, and the pharmacokinetics of the administered activity of radiolabeled antibodies. Therefore, the topics addressed in this review include: (1) Volume determinations of tumors and normal organs from x-ray-computed tomography and magnetic resonance imaging, (2) quantitation of the activity of radiolabeled antibodies in tumors and normal organs from planar gamma camera views, (3) quantitative single-photon emission computed tomography and positron emission tomography, (4) correlative image analysis, and (5) treatment planning in clinical radioimmunotherapy.

  20. Developmental immunotoxicology assessment of rituximab in cynomolgus monkeys.

    PubMed

    Vaidyanathan, Anu; McKeever, Kathleen; Anand, Banmeet; Eppler, Steve; Weinbauer, Gerhard F; Beyer, Joseph C

    2011-01-01

    Rituximab is a chimeric murine/human-engineered immunoglobulin (Ig) G1 anti-CD20 monoclonal antibody, selectively depleting CD20-expressing cells in peripheral blood and lymphoid tissues. As part of the rituximab registration-enabling program for rheumatoid arthritis, cynomolgus monkey embryo-fetal development and pre- and postnatal developmental toxicity studies were performed. In both studies, female cynomolgus monkeys were administered rituximab iv at doses of 0/0, 15/20, 37.5/50, and 75/100 mg/kg (loading dose/study dose) from gestation day (GD) 20 to 50 for the embryo-fetal development study and GD 20 to postpartum (pp) day 28 for the pre- and postnatal study. In the embryo-fetal development study, although maternal dosing ended during the first trimester at GD 50, placental transfer of rituximab to fetuses was demonstrated at GD 100. Consequently, fetuses demonstrated B-cell depletion in lymphoid tissues at GD 100. Repletion of B cells was demonstrated in infants in a follow-up pre- and postnatal study following fetal and neonatal exposure. In the pre- and postnatal study, despite B-cell depletion, there was no significant functional consequence on the infant's ability to mount T-cell-dependent antibody responses following vaccination or antigenic challenge. Overall, rituximab was well tolerated at maximum feasible doses up to 100 mg/kg in pregnant cynomolgus monkeys and their infants after exposure from the period of organogenesis throughout pregnancy, parturition, and postnatal development. Importantly, the preclinical data have been concordant with the clinical data in children for cases where rituximab was administered during pregnancy. PMID:20937725

  1. Improving testing for hepatitis B before treatment with rituximab

    PubMed Central

    Jopson, Laura; Ng, Sarah; Lowery, Matthew; Harwood, Jayne; Waugh, Sheila; Valappil, Manoj; McPherson, Stuart

    2016-01-01

    Aims/Objectives/Background Individuals with current or previous infection with the hepatitis B virus (HBV) can experience viral reactivation when treated with immunosuppression. Rituximab, an anti-CD20 antibody used to treat many diseases, has potent immunosuppressant effects with a high risk of causing HBV reactivation. Reactivation can range from elevated liver enzymes to acute severe hepatitis with liver failure and a significant mortality risk. HBV screening and appropriate use of prophylactic antiviral therapy can prevent reactivation. This work describes the introduction of a local policy for HBV testing in patients before rituximab treatment and assesses its impact. Methods and Results A baseline review (before policy introduction) of 90 patients showed that only 21 (23%) had hepatitis B surface antigen (HBsAg) and 17 (19%) had hepatitis B core antibody (anti-HBcAb) tested before receiving rituximab. Following introduction of the policy (on the basis of international guidelines), improved laboratory reporting protocols and targeted education sessions, two further reviews of HBV testing rates among patients being initiated onto rituximab were performed. There was a marked increase in pre-rituximab testing for HBsAg from 23 to 79% and for anti-HBcAb from 19 to 78%. Throughout the study period, a total of one (0.8%) HBsAg-positive and six (4.7%) anti-HBcAb-positive patients were identified. Conclusions This work clearly indicates that simple strategies can markedly improve appropriate HBV screening. In our cohort, 6% (of whom only 43% had recognized HBV risk factors) required antiviral prophylaxis, which emphasizes the importance of universal screening before rituximab. Reinforcement of the guidelines and ongoing education is needed to further increase testing rates. PMID:27388147

  2. Rituximab and biosimilars – equivalence and reciprocity

    PubMed Central

    Qureshi, Zaina P; Magwood, Jametta S; Singh, Sarveshwari; Bennett, Charles L

    2014-01-01

    Cancer is a debilitating disease affecting millions of people daily. Over the years, cancer treatment has advanced in leaps and bounds. Antibodies are important breakthrough therapeutic agents for cancer. These agents, proteins produced by B lymphocytes of the immune system in response to antigens, bind to receptors on cell surfaces so that the antigen–antibody complexes can be recognized and destroyed by phagocytes. While each B cell synthesizes only one kind of antibody, an entire population of different types of B cells and their respective antibodies are produced in response to various antigens to which the organism had been exposed. However, to be useful clinically, substantial amounts of a single antibody must be generated from a single ancestral B cell. These antibodies produced by a specific population of B cells are the monoclonal antibodies that have become the cornerstone of treatment for cancer and many immunologic illnesses. The purpose of this report is to provide an overview of the clinical development of biosimilars in clinical oncology, focusing on rituximab and like biosimilars. PMID:24829884

  3. Radioimmunotherapy: potential as a therapeutic strategy in non-Hodgkin's lymphoma.

    PubMed

    Wun, T; Kwon, D S; Tuscano, J M

    2001-01-01

    Lymphomas are the fifth most common malignancy in the United States and are increasing in incidence. Despite being among the most responsive malignancies to radiation and chemotherapy, the majority of patients relapse or have progressive disease. Monoclonal antibodies (MAbs) directed at cell-specific surface antigens have been useful in the diagnosis of lymphomas and, more recently, the therapeutic mouse-human chimeric MAb rituximab has demonstrated effectiveness in B cell lymphomas. Conjugating MAbs to radionuclides is a strategy for improving the efficacy of MAb lymphoma therapy by delivering radiation in close proximity to the tumour (radioimmunotherapy or RIT). In addition, the low dose rate of the delivered radiation may exert a greater antitumour activity than an equivalent dose of conventional external beam radiation. The antigenic targets for MAb therapy have included CD20, CD22, HLA-DR, and B cell idiotype. Radionuclides that have been used include iodine-131, yttrium-90, and copper-67; there are relative merits and disadvantages to each source of radiation. Clinical studies to date have focused on relapsed and refractory patients with both indolent and aggressive lymphomas, although more recent studies have included previously untreated patients with indolent lymphoma. Radioimmunoconjugate has been delivered as either single or multiple doses. Response rates have varied widely, dependent on the patient population and the response criteria. Of note, complete responses can be achieved in this typically refractory patient group. Toxicities have generally consisted of mild infusion-related nausea, fever, chills, and asthenia. Neutropenia and thrombocytopenia are the dose-limiting toxicities and have prompted the incorporation of autologous stem cell support as a means of achieving dose escalation. To date, RIT has been delivered to highly selected patients in relatively few centres with requisite equipment and specialised personnel. In addition to these

  4. Treatment planning for radio-immunotherapy

    NASA Astrophysics Data System (ADS)

    Erdi, Alev K.; Erdi, Yusuf E.; Yorke, Ellen D.; Wessels, Barry W.

    1996-10-01

    To foster the success of clinical trials in radio-immunotherapy (RIT), one needs to determine (i) the quantity and spatial distribution of the administered radionuclide carrier in the patient over time, (ii) the absorbed dose in the tumour sites and critical organs based on this distribution and (iii) the volume of tumour mass(es) and normal organs from computerized tomography or magnetic resonance imaging and appropriately correlated with nuclear medicine imaging techniques (such as planar, single-photon emission computerized tomography or positron-emission tomography). Treatment planning for RIT has become an important tool in predicting the relative benefit of therapy based on individualized dosimetry as derived from diagnostic, pre-therapy administration of the radiolabelled antibody. This allows the investigator to pre-select those patients who have `favourable' dosimetry characteristics (high time-averaged target: non-target ratios) so that the chances for treatment success may be more accurately quantified before placing the patient at risk for treatment-related organ toxicities. The future prospects for RIT treatment planning may yield a more accurate correlation of response and critical organ toxicity with computed absorbed dose, and the compilation of dose - volume histogram information for tumour(s) and normal organ(s) such that computing tumour control probabilities and normal tissue complication probabilities becomes possible for heterogeneous distributions of the radiolabelled antibody. Additionally, radiobiological consequences of depositing absorbed doses from exponentially decaying sources must be factored into the interpretation when trying to compute the effects of standard external beam isodose display patterns combined with those associated with RIT.

  5. Sarcoidosis following successful treatment of pemphigus vulgaris with rituximab: a rituximab-induced reaction further supporting B-cell contribution to sarcoidosis pathogenesis?

    PubMed

    Galimberti, F; Fernandez, A P

    2016-06-01

    The anti-CD20 peripheral B-cell depleting monoclonal antibody, rituximab, has been shown to be a safe and effective treatment for refractory pemphigus vulgaris (PV), a potentially fatal autoimmune blistering disease. We report a patient who developed skin nodules and arthralgias following successful treatment of refractory PV with rituximab. Clinical, serological and histological findings were consistent with a diagnosis of sarcoidosis. The nodules promptly responded to treatment with corticosteroids, and resolved without recurrence when the medication was tapered several months later. The temporal onset of sarcoidosis following treatment with rituximab and the eventual resolution, coupled with the remarkable similarities between the B-cell immunological environment expected in our patient during the post-rituximab period and the immunological environment described in patients with idiopathic sarcoidosis, strongly implicates exposure to rituximab as the trigger for sarcoidosis development in our patient. We propose that rituximab-induced sarcoidal granulomas may be a rare adverse effect of treatment with this medication, providing further support for an important role of B cells in the pathogenesis of sarcoidosis. With better understanding of the circumstances surrounding sarcoidosis development following rituximab administration, this medication could potentially be used to induce sarcoidosis in animal research models to study the immunopathogenesis of this disease. PMID:26800651

  6. Criteria for the selection of radionuclides for tumor radioimmunotherapy

    SciTech Connect

    Srivastava, S.C.; Mausner, L.F.; Mease, R.C.

    1991-01-01

    The potential of utilizing monoclonal antibodies as carriers of radionuclides for the selective destruction of tumors (radioimmunotherapy, RIT) has stimulated much research activity. From dosimetric and other considerations, the choice of radiolabel is an important factor that needs to be optimized for maximum effectiveness of RIT. This paper reviews and assesses a number of present and future radionuclides that are particularly suitable for RIT based on the various physical, chemical, and biological considerations. Intermediate to high-energy beta emitters' (with and without gamma photons in their emission) are emphasized since they possess a number of advantages over alpha and Auger emitters. Factors relating to the production and availability of candidate radiometals as well as their stable chemical attachment to monoclonal antibodies are discussed. 34 refs., 4 tabs.

  7. Development and evaluation of copper-67 and samarium-153 labeled conjugates for tumor radioimmunotherapy

    SciTech Connect

    Srivastava, S.C.; Mausner, L.F.; Mease, R.C.; Meinken, G.E.; Joshi, V.; Kolsky, K.; Sweet, M.; Steplewski, Z.

    1995-02-01

    The potential of utilizing receptor-specific agents such as monoclonal antibodies (MAb), and MAb-derived smaller molecules, as carriers of radionuclides for the selective destruction of tumors has stimulated much research activity. The success of such applications depends on many factors, especially the tumor binding properties of the antibody reagent, the efficiency of labeling and in-vivo stability of the radioconjugate and, on the careful choice of the radionuclide best suited to treat the tumor under consideration. The radiolabeled antibody technique for radioimmunotherapy (RIT), however, has experienced many limitations, and its success has not matched the expectations that were raised more than a decade ago. The problems that have been identified include: (i) degradation of antibody immunoreactivity resulting from chemical manipulations required for labeling; (ii) lack of suitable radioisotopes and methods for stable attachment of the radiolabel; (iii) in-vivo instability of the radioimmunoconjugates; (iv) excessive accumulation of activity in non-target locations; and (v) lack of radioimmunoconjugate accessibility to cells internal to a tumor mass. A careful choice of the radionuclide(s) best suited to treat the tumor under consideration is one of the most important requirements for successful radioimmunotherapy. This study evaluates copper 67 and samarium 153 for tumor radioimmunotherapy.

  8. Rituximab-associated acute thrombocytopenia: an under-diagnosed phenomenon.

    PubMed

    Ram, Ron; Bonstein, Lilach; Gafter-Gvili, Anat; Ben-Bassat, Isaac; Shpilberg, Ofer; Raanani, Pia

    2009-04-01

    Acute infusion reactions are the most common documented adverse reactions reported with rituximab, with overt cytokine release syndrome, and hematological adverse events being much rarer. The clinical course of a patient with mantle cell lymphoma, who developed acute thrombocytopenia and leukopenia following rituximab administration, is described and the literature reviewed. Serum complement and the levels of three cytokines--TNF-alpha, IL-6, and IL-1, were measured 2 days after the infusion of rituximab by using ELISA assay. Drug-dependent antibodies against platelets were evaluated by two procedures as follows: an immunofluorescence test applying flow cytometry and Monoclonal Antibody Immobilization of Platelet Antigen (MAIPA). Serum levels of TNF-a were significantly increased compared with normal, whereas those of IL-6 and IL-1 were not increased significantly. Flow cytometry assay and the MAIPA assay failed to detect rituximab-dependent antibodies against platelets. Complement levels were decreased compared with normal. Literature search yielded 10 publications reporting on another 15 patients. The most common type of lymphoma was mantle cell lymphoma, six patients had bone marrow involvement, and 10 patients had splenomegaly. In 10 patients, acute cytopenia was preceded by cytokine release syndrome or infusion-related symptoms. Usually, thrombocytopenia was not associated with bleeding manifestations. Thrombocytopenia was the most commonly acute cytopenia reported. The postulated pathogenesis is associated with cytokine release syndrome and complement activation. Patients with potential risk factors like splenomegaly and bone marrow involvement, who develop clinical manifestations compatible with cytokine release syndrome, should be closely monitored for rituximab-associated cytopenia. PMID:19260124

  9. Persistence of babesiosis for >2 years in a patient on rituximab for rheumatoid arthritis.

    PubMed

    Raffalli, John; Wormser, Gary P

    2016-06-01

    We report a patient who was being treated with rituximab for rheumatoid arthritis who developed Babesia microti infection that persisted for 26 months despite prolonged anti-babesia drug therapy. The explanation for the persistence was likely to have been the long-term immunocompromising effects of rituximab, as evidenced by seronegativity for B. microti antibodies that lasted for more than 1 year after onset of infection. PMID:27036977

  10. Macrodosimetry and microdosimetry in radioimmunotherapy

    SciTech Connect

    Leichner, P.K.

    1990-02-01

    This progress report summarizes the research accomplished and its clinical implementation since July 15, 1989. To improve beta-particle dosimetry, a point-source function was developed that is valid for a wide range of beta-particle emitters. An analytical solution for beta-particle dose rates within and outside of slabs of finite thickness was validated in an experimental tumor system and is now being used in clinical radioimmunotherapy (RIT). Quantitative SPECT was validated in phantom studies, beagle dogs, and patients with Kaposi's sarcoma. It is currently being used in clinical RIT for patients with Hodgkin's disease or hepatoma. Additionally, methodologies and computer software are being developed for quantitative autoradiography to achieve absorbed-dose calculation on the cellular level. 7 refs., 1 tab.

  11. Radioimmunotherapy for hematopoietic cell transplantation.

    PubMed

    Jurcic, Joseph G

    2013-04-01

    Radioimmunotherapy (RIT) represents an attractive strategy to deliver radiation selectively to tumor and other target organs while minimizing toxicity to normal tissues. RIT with β-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of conditioning before hematopoietic cell transplantation (HCT) in leukemia. Similarly, RIT directed against CD20 has shown promise in the setting of autologous and allogeneic HCT for B-cell lymphomas. α-particle immunotherapy with isotopes such as bismuth-213, actinium-225 and astatinine-211 offers the possibility of more selective and efficient killing of target cells while sparing the surrounding normal cells. Pretargeting strategies may further improve target:normal organ dose ratios. While RIT has demonstrated significant antitumor activity, ultimately, randomized studies will be required to determine if conditioning regimens that include this therapeutic modality can improve patient outcomes after HCT. PMID:23557421

  12. The risk of infections in hematologic patients treated with rituximab is not influenced by cumulative rituximab dosage - a single center experience

    PubMed Central

    2014-01-01

    Background Rituximab, a monoclonal antibody directed against CD20, is approved for the treatment of CD20-positive B-cell Non-Hodgkin’s lymphoma and rheumatologic disorders. Due to its potent activity in depleting CD20-positive lymphocytes, the influence on opportunistic infections is still under discussion. Thus, we analyzed the impact of rituximab either as monotherapy or in combination with other chemotherapeutic regimens to elucidate its role in contributing to infectious complications. Methods The records of consecutive patients (n = 125, 141 treatment episodes) treated with rituximab alone or in combination with chemotherapy and corticosteroids were analyzed retrospectively for the incidence, spectrum and outcome of infections during treatment and 6 months after the last course of rituximab. Univariate analysis of cofactors such as steroid medication, antiinfective prophylaxis, underlying disease and remission status were performed. Results Altogether 80 therapy episodes were associated with infections, the median number of infections per patient being 1 (range 1–7). The number of infectious complications was significantly higher in patients receiving a combination of rituximab and chemotherapy compared to rituximab monotherapy (p < 0.001). There was no statistically significant difference regarding number of rituximab courses or cumulative rituximab dosage between episodes with and without infections, respectively.Mean cumulative prednisone dosage between the cohort with infections and the one without infections showed a trend towards higher dosage of prednisone in the patients with infections (mean difference 441 mg, p > 0.14). Conclusions Rituximab in induction treatment, either as monotherapy or combined with chemotherapy by itself does not increase the incidence or change the spectrum of infections in hematologic patients. However the possible influence of higher dosages of concomitant steroid medication on frequency of infections

  13. Selective response to rituximab in a young child with MuSK-associated myasthenia gravis.

    PubMed

    Govindarajan, Raghav; Iyadurai, Stanley J; Connolly, Anne; Zaidman, Craig

    2015-08-01

    Neuromuscular junction disorders in children are either genetic, such as congenital myasthenic syndrome, or autoimmune with circulating antibodies most commonly against acetylcholine receptors. There is limited experience recognizing and treating children with myasthenia associated with muscle-specific tyrosine kinase antibodies. We report a seven-year-old child with intermittent esotropia since age 3 months, and two years of progressive and severe diplopia, dysarthria, dysphagia, and facial weakness. Acetylcholine receptor antibodies and genetic testing for congenital myasthenic syndrome were negative. Muscle specific tyrosine kinase antibodies were significantly elevated. Ophthalmoplegia and bulbar weakness were refractory to treatment with acetylcholinesterase inhibitors, corticosteroids and IVIg but completely resolved following treatment with rituximab. Her neurologic examination remained normal at the most recent follow-up, 15 months after initiation of rituximab. Children with MuSK myasthenia, like adults, can respond to rituximab despite long standing disease and failure to improve on other immunosuppressant medications. PMID:25998611

  14. Improved production, and evaluation of Cu-67 for tumor radioimmunotherapy

    SciTech Connect

    Kolsky, K.L.; Joshi, V.; Meinken, G.E.

    1994-05-01

    Copper-67 is a radionuclide of great interest for radioimmunotherapy. We report labeling and biodistribution results with the anti-CEA F(ab`){sub 2} monoclonal antibody (MAb). The anti-CEA F(ab`){sub 2} MAb was conjugated with 1,4,7,10-tetraazacyclodo-decane-and 1,4,8,11-tetraazacyclotetradecane-N,N`,N``,N```-tetraacetic acid (DOTA and TETA) using their mono NHS esters. The ligands were synthesized using a simple large scale method and the MAb conjugates were labeled with Cu-67 (90{plus_minus}5% yield, 98% in-vitro serum stability at 4d, and immunoreactivity 80{plus_minus}10%). Data in tumor (LS-174 T cells) xenografted nude mice showed similar tumor uptake (% ID/g) for both DOTA and TETA at 24h (32.4 vs 35.7) and 96h (14.6 vs 17.1). The DOTA conjugate showed slightly higher liver uptake (24h: 14.7 vs 10.4; 96h: 7.05 vs 5.3) and blood uptake (24h: 6.16 vs 4.73; 96h: 0.72 vs 0.46) while the TETA conjugate showed higher kidney uptake (24h: 12.8 vs 4.8; 96h: 8.6 vs 4.1). These results are quite favorable and warrant further study of these Cu-67-MAb conjugates for radioimmunotherapy.

  15. PET/CT AND RADIOIMMUNOTHERAPY OF PROSTATE CANCER

    PubMed Central

    Bouchelouche, Kirsten; Capala, Jacek; Oehr, Peter

    2009-01-01

    Purpose of review Traditional morphologically based imaging modalities are now being complemented by positron emission tomography (PET)/computerized tomography (CT) in prostate cancer. Metastatic prostate cancer is an attractive target for radioimmunotherapy (RIT) since no effective therapies are available. This review highlights the most important achievements within the last year in PET/CT and RIT of prostate cancer. Recent findings Conflicting results exist on the use of choline for detection of malignant disease in the prostate gland. The role of PET/CT in N-staging remains to be elucidated further. However, 18F-choline and 11C-choline PET/CT have been demonstrated to be useful for detection of recurrence. 18F-choline and 18F-fluoride PET/CT are useful for detection of bone metastases. Prostate tumor antigens may be used as targets for RIT. Prostate specific membrane antigen (PSMA) is currently under focus of a number of diagnostic and therapeutic strategies. J591, a monoclonal antibody, that targets the extracellular domain of PSMA, shows promising results. HER2 receptors may also have a potential as target for PET/CT imaging and RIT of advanced prostate cancer. Summary PET/CT in prostate cancer has proven to play a significant role, in particular for detection of prostate cancer recurrence and bone metastases. Radioimmunotherapy of metastatic prostate cancer warrant further investigations. PMID:19535981

  16. Cancer radioimmunotherapy with alpha-emitting nuclides.

    PubMed

    Couturier, Olivier; Supiot, Stéphane; Degraef-Mougin, Marie; Faivre-Chauvet, Alain; Carlier, Thomas; Chatal, Jean-François; Davodeau, François; Cherel, Michel

    2005-05-01

    In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with beta-emitters for the treatment of refractory cases. The development of novel RIT with alpha-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with alpha-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of alpha-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an alpha-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with alpha-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of alpha-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies. PMID:15841373

  17. Subcutaneous versus intravenous administration of rituximab: pharmacokinetics, CD20 target coverage and B-cell depletion in cynomolgus monkeys.

    PubMed

    Mao, Cheng-Ping; Brovarney, Martin R; Dabbagh, Karim; Birnböck, Herbert F; Richter, Wolfgang F; Del Nagro, Christopher J

    2013-01-01

    The CD20-specific monoclonal antibody rituximab (MabThera(®), Rituxan(®)) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4-6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite

  18. Subcutaneous versus Intravenous Administration of Rituximab: Pharmacokinetics, CD20 Target Coverage and B-Cell Depletion in Cynomolgus Monkeys

    PubMed Central

    Mao, Cheng-Ping; Brovarney, Martin R.; Dabbagh, Karim; Birnböck, Herbert F.; Richter, Wolfgang F.; Del Nagro, Christopher J.

    2013-01-01

    The CD20-specific monoclonal antibody rituximab (MabThera®, Rituxan®) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4–6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite

  19. Radioimmunotherapy

    MedlinePlus

    ... will be involved in this procedure? A radiologist, nuclear medicine physician or radiation oncologist and other healthcare ... equipment? A radiologist who has specialized training in nuclear medicine or a nuclear medicine physician will supervise ...

  20. Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with {sup 211}At-MX35 F(ab'){sub 2}

    SciTech Connect

    Elgqvist, Joergen . E-mail: jorgen.elgqvist@radfys.gu.se; Andersson, Hakan; Bernhardt, Peter; Baeck, Tom; Claesson, Ingela; Hultborn, Ragnar; Jensen, Holger; Johansson, Bengt R.; Lindegren, Sture; Olsson, Marita; Palm, Stig; Warnhammar, Elisabet; Jacobsson, Lars

    2006-11-15

    Purpose: To elucidate the therapeutic efficacy of {alpha}-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the {alpha}-particle emitter Astatine-211 ({sup 211}At) labeled to the mAb MX35 F(ab'){sub 2}. Methods and Materials: Animals were inoculated intraperitoneally with {approx}1 x 10{sup 7} cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100, or 200 kBq {sup 211}At-MX35 F(ab'){sub 2} (n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq {sup 211}At-Rituximab F(ab'){sub 2} (n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors and ascites was determined. An MCP model was developed and compared with the experimentally determined tumor-free fraction (TFF). Results: When treatment was given 4 weeks after cell inoculation, the TFFs were 25%, 22%, 50%, and 61% after treatment with 25, 50, 100, or 200 kBq {sup 211}At-MX35 F(ab'){sub 2}, respectively, the specific energy to irradiated cell nuclei varying between {approx}2 and {approx}400 Gy. Conclusion: As a significant increase in the therapeutic efficacy was observed between the activity levels of 50 and 100 kBq (TFF increase from 22% to 50%), the conclusion was that the MRA is {approx}100 kBq {sup 211}At-MX35 F(ab'){sub 2}. MCP was most consistent with the TFF when assuming a diffusion depth of 30 {mu}m of the mAbs in the tumors.

  1. Radioimmunotherapy: Development of an effective approach. Progress report, 1987

    SciTech Connect

    Not Available

    1987-12-31

    Goals of this program are to answer the fundamental scientific questions for the development of an effective approach for delivering radiation therapy to cancer on antibody-based radiopharmaceuticals. The following list consists of highlights of developments from our program: documented therapeutic response of lymphoma in patients receiving radioimmunotherapy; development and application of quantitative radionuclide imaging techniques for therapy planning and dosimetry calculations; multicompartmental modeling and analysis of the in vivo MoAb kinetics in patients; a MoAb macrocycle chelate for Cu-67: development, production, in vitro and in vivo testing; NMR analysis of immunoradiotherapeutic effects on the metabolism of lymphoma; analysis of the variable molecular characteristics of the MoAb radiopharmaceutical, and their significance; in vivo studies in mice and patients of the metabolism of radioiodinated MoAb as well as In-111 CITC MoAb; and biodistribution of Cu-67 TETA MoAb in nude mice with human lymphoma.

  2. Effect of taxol on the therapeutic efficacy of radioimmunotherapy

    SciTech Connect

    Cheng, K.T.; Spicer, K.M.; Means, J.

    1994-05-01

    This investigation was conducted to evaluate the potential of using taxol to maximize the therapeutic effectiveness of radioimmunotherapy. Published studies have shown taxol to be an effective radiosensitizer of tumors to external irradiation by blocking tumor cells in the G{sub 2}/M phases of the cell cycle. In vitro and in vivo studies were carried out to study the effect of low-dose taxol on the therapeutic effectiveness of I-131 anti-CEA monoclonal antibody (OEM-094-20856 MoAb) of human colonic carcinoma (LS-174T cell line). The in vitro clonogenic assay studies indicated taxol effectively enhanced the cell killing effect of I-131 MoAb.

  3. Criteria for the selection of nuclides for radioimmunotherapy

    SciTech Connect

    Adelstein, S.J.; Kassis, A.I.

    1986-01-01

    This report describes many factors that need to be considered if radioimmunotherapy is to become a commonplace reality. For beta-emitting radionuclides, two physical features of importance are half-life and energy, with the latter determining the range. These features must be matched to the pharmacokinetics of the carrier and the distribution of the radionuclide, both macroscopically and microscopically. Alpha-particle emitters could be considered for cells that are readily accessible to the labeled antibody and for populations that uniformly and constantly display the targeted antigen or idiotype, e.g., trafficking cells such as T or B lymphocytes. For cells that concentrate the radioactive label, the use of low-energy electrons should be examined. If the radionuclide is translocated to the nucleus, the Auger effect can be particularly lethal because of the high LET-like biological response. 15 refs., 3 figs., 2 tabs.

  4. Favorable outcome of granulocyte colony-stimulating factor use in neuromyelitis optica patients presenting with agranulocytosis in the setting of rituximab.

    PubMed

    Mealy, Maureen A; Levy, Michael

    2015-10-15

    Neuromyelitis optica is a severe autoimmune condition affecting the central nervous system characterized by a relapsing disease course. Rituximab is a chimeric monoclonal antibody against the protein CD20, and is one of the most utilized medications for management of this disease. A known complication of rituximab use is neutropenia. We report on two patients who developed symptomatic early-onset rituximab-induced agranulocytosis who safely received granulocyte colony-stimulating factor. Neutrophil counts recovered quickly and both patients continue to receive rituximab without further incident. PMID:26439958

  5. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis

    PubMed Central

    Naismith, R.T.; Piccio, L.; Lyons, J.A.; Lauber, J.; Tutlam, N.T.; Parks, B.J.; Trinkaus, K.; Song, S.K.; Cross, A.H.

    2010-01-01

    Objective: B cells and the humoral immune system have been implicated in the pathogenesis of multiple sclerosis (MS). This study sought to evaluate the efficacy, safety, and tolerability of add-on therapy with rituximab, a monoclonal antibody that depletes circulating B cells, in subjects with relapsing MS with breakthrough disease defined by clinical and MRI activity (Class III evidence). Methods: Thirty subjects with a relapse within the past 18 months despite use of an injectable disease-modifying agent, and with at least 1 gadolinium-enhancing (GdE) lesion on any of 3 pretreatment MRIs, received rituximab administered at 375 mg/m2 weekly × 4 doses. Three monthly posttreatment brain MRI scans were obtained beginning 12 weeks after the first infusion. Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) were obtained at baseline and throughout the posttreatment follow-up. Results: GdE lesions were reduced after treatment with rituximab, with 74% of posttreatment MRI scans being free of GdE activity compared with 26% free of GdE activity at baseline (p < 0.0001). Median GdE lesions were reduced from 1.0 to 0, and mean number was reduced from 2.81 per month to 0.33 after treatment (88% reduction). MSFC improved as well (p = 0.02). EDSS remained stable. Conclusion: Rituximab add-on therapy was effective based upon blinded radiologic endpoints in this phase II study. In combination with standard injectable therapies, rituximab was well-tolerated with no serious adverse events. B-cell–modulating therapy remains a potential option for treatment of patients with relapsing MS with an inadequate response to standard injectable therapies. Classification of evidence: This study provides Class III evidence that add-on rituximab reduces gadolinium-enhancing brain lesions in multiple sclerosis. GLOSSARY DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; FOV = field of view; GdE = gadolinium-enhancing; HACA = human

  6. Efficacy and safety of 90Y ibritumomab tiuxetan (Zevalin) radioimmunotherapy for non-Hodgkin's lymphoma.

    PubMed

    Witzig, Thomas E

    2003-12-01

    Radioimmunotherapy, an emerging treatment option for certain patients with non-Hodgkin's lymphoma (NHL), enables the targeting of cytotoxic radiation to tumor cells with minimal irradiation of normal cells. Yttrium 90 ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, Cambridge, MA) was approved in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory NHL. Yttrium 90 ibritumomab tiuxetan is an effective treatment with a consistent overall response rate of 73% to 83%. It has a good safety profile and is generally well tolerated in the indicated population. The results of clinical trials show that (90)Y ibritumomab tiuxetan can be used effectively and safely in many patients with NHL, including those with mild thrombocytopenia and those with disease that is refractory to rituximab, without the adverse events associated with conventional chemotherapy and external beam radiation therapy. The use of (90)Y ibritumomab tiuxetan does not preclude subsequent therapy with other conventional treatment options. PMID:14710398

  7. Gemcitabine enhances rituximab-mediated complement-dependent cytotoxicity to B cell lymphoma by CD20 upregulation.

    PubMed

    Hayashi, Kazumi; Nagasaki, Eijiro; Kan, Shin; Ito, Masaki; Kamata, Yuko; Homma, Sadamu; Aiba, Keisuke

    2016-05-01

    Although rituximab, a chimeric monoclonal antibody that specifically binds to CD20, has significantly improved the prognosis for diffuse large B cell lymphoma (DLBCL), one-third of DLBCL patients demonstrate resistance to rituximab or relapse after rituximab treatment. Thus, a novel approach to rituximab-based treatment is likely to be required to improve the efficacy of DLBCL treatment. As complement dependent cytotoxicity (CDC) is a key mechanism mediating rituximab's tumoricidal activity, rituximab binding to CD20 on tumor cells is a critical factor for effective rituximab-based treatments against DLBCL. We found that gemcitabine (GEM), but not lenalidomide (LEN) or azacitidine (AZA), can upregulate CD20 expression in TK and KML-1 cells, two human DLBCL cell lines. Treatment of TK and KML-1 cells with GEM enhanced CD20 expression at both the mRNA and protein levels. CD20 upregulation by GEM treatment was accompanied by increased rituximab binding to CD20. In TK cells, GEM treatment synergistically increased rituximab-mediated CDC activity in a dose-dependent manner. In KML cells, GEM treatment also induced upregulation of complement regulatory proteins, possibly leading to resistance to CDC. Treatment with LEN, a drug that did not upregulate CD20, did not enhance rituximab-mediated CDC activity. GEM treatment activated nuclear factor-kappa B (NF-kB) signaling in these cells. Furthermore, a specific inhibitor to NF-kB suppressed GEM-induced CD20 upregulation, indicating that GEM-induced NF-kB activation is closely associated with CD20 upregulation. These results suggest that when used in combination, GEM might enhance the antitumor efficacy of rituximab against DLBCL due to its unique ability to upregulate CD20. PMID:26920337

  8. AFM analysis of the multiple types of molecular interactions involved in rituximab lymphoma therapy on patient tumor cells and NK cells.

    PubMed

    Li, Mi; Xiao, Xiubin; Zhang, Weijing; Liu, Lianqing; Xi, Ning; Wang, Yuechao

    2014-08-01

    Rituximab is a monoclonal antibody drug approved for the treatment of patients with lymphomas. Rituximab's main killing mechanism is antibody-dependent cellular cytotoxicity (ADCC). During ADCC, rituximab's fragment antigen binding (Fab) region binds to the CD20 antigen on the tumor cell and its fragment crystallizable (Fc) region binds to the Fc receptor (FcR) on the natural killer (NK) cells. In this study, two types of molecular interactions (CD20-rituximab, FcR-rituximab) involved in ADCC were measured simultaneously on cells prepared from biopsy specimens of lymphoma patients by utilizing atomic force microscopy (AFM) with functionalized tips carrying rituximab. NK cells were detected by specific NKp46 fluorescent labeling and tumor cells were detected by specific ROR1 fluorescent labeling. Based on the fluorescence recognition, the binding affinity and distribution of FcRs on NK cells, and CD20 on tumor cells, were quantitatively measured and mapped. The binding affinity and distribution of FcRs (on NK cells) and CD20 (on tumor cells) were associated with rituximab clinical efficacy. The experimental results provide a new approach to simultaneously quantify the multiple types of molecular interactions involved in rituximab ADCC mechanism on patient biopsy cells, which is of potential clinical significance to predict rituximab efficacy for personalized medicine. PMID:25117605

  9. Long-term radioimmunotherapy studies of Cu-64 anti-colon carcinoma monoclonal antibody (MAb)-1A3, intact and F(ab{prime}){sub 2} singly and in combination, in the GW39-hamster model

    SciTech Connect

    Connett, J.M.; Anderson, C.J.; Guo, L.W.

    1996-05-01

    In previous studies we have shown that Cu-64 has potential for use in radioimmunotherapy (RIT). The present study was undertaken to examine the therapeutic potential of Cu-64-benzyl-TETA-MAb 1A3, intact and F(ab{prime}){sub 2} fragments, injected single or in combination. Using the model of hamsters carrying the GW39 human colon carcinoma in their thighs, we were interested in whether injecting Cu-64-MAb 1A3 intact and F(ab{prime}){sub 2} fragments together would give improved RIT results compared to either agent alone due to the better tumor penetrating properties of F(ab{prime}){sub 2} fragments and the higher uptake and long tumor residence time of intact MAbs. Hamsters were injected with either 1.5 mCi Cu-64-1A3, 1.5 mCi Cu-64-1A3 F(ab{prime}){sub 2} or a combination of 0.75 mCi Cu-64-1A3 intact and 0.75 mCi Cu-64-1A3 F(ab{prime}){sub 2}. These suboptimal doses of Cu-64 were administered in order to detect any enhanced RIT effects with the combination of Cu-64-labeled MAb and fragments. Control groups received saline along. Hamsters were sacrificed when tumors were > 10 g or after surviving for 6 months. Mean lifespans for hamsters treated with Cu-64-1A3 intact, F(ab{prime}){sub 2}, and the combination were 92 {plus_minus} 44 days, 104 {plus_minus} 54 days and 129 {plus_minus} 48 days respectively, compared to 32 {plus_minus} 5 days for the saline controls (p,0.001). 6 months following treatment 43% of the hamsters (3/7) treated with 1.5 mCi Cu-64 1A3 F(ab{prime}){sub 2}, and 50% of hamsters (5/10) treated with 0.75 mCi Cu-64-1A3 and 0.75 mCi Cu-64-1A3 F(ab{prime}){sub 2} in combination were alive and tumor free. Although tumor grown inhibition was also seen in the group receiving 1.5 mCi Cu-64 1A3 intact, only one hamster (1/7) survived tumor free to 6 months. Results show that Cu-64-1A3 F(ab{prime}){sub 2} as well as intact Cu-64-1A3 can increase survival and effect long term tumor inhibition.

  10. Place in therapy of rituximab in the treatment of granulomatosis with polyangiitis and microscopic polyangiitis

    PubMed Central

    Shah, Shivani; Geetha, Duvuru

    2015-01-01

    Granulomatosis with polyangiitis and microscopic polyangiitis are small vessel vasculitides characterized by circulating antineutrophil circulating antibodies. Standard treatment for active severe disease has consisted of cyclophosphamide with glucocorticoids with or without plasmapheresis, which achieves approximately 75% sustained remission, but carries significant adverse effects such as malignancy, infertility, leukopenia, and infections. The role of B cells in the pathogenesis of anti-neutrophil circulating antibodies-associated vasculitis has been established, and as such, rituximab, a monoclonal anti-CD20 antibody, has been studied in treatment of active granulomatosis with polyangiitis and microscopic polyangiitis (induction) and in maintaining remission. Rituximab has been shown to be effective in inducing remission in several retrospective studies in patients with refractory disease or cyclophosphamide intolerance. The RAVE and RITUXVAS trials demonstrated rituximab is a noninferior alternative to standard cyclophosphamide-based therapy; however, its role in elderly patients and patients with severe renal disease warrants further investigation. Rituximab has been compared with azathioprine for maintaining remission in the MAINRITSAN trial and may be more efficacious in maintaining remission in patients treated with cyclophosphamide induction. Rituximab is not without risks and carries a similar adverse event risk rate as cyclophosphamide in randomized control trials. However, its use can be considered over cyclophosphamide in patients who have relapsing or refractory disease or in young patients seeking to preserve fertility.

  11. Antibody

    MedlinePlus

    An antibody is a protein produced by the body's immune system when it detects harmful substances, called antigens. Examples ... microorganisms (bacteria, fungi, parasites, and viruses) and chemicals. Antibodies may be produced when the immune system mistakenly ...

  12. Rituximab-Induced Splenic Rupture and Cytokine Release

    PubMed Central

    Nair, Ranjit; Gheith, Shereen; Lamparella, Nicholas

    2016-01-01

    Patient: Female, 55 Final Diagnosis: Mantle cell lymphoma Symptoms: Cytokine release syndrome • hypoglycemia • hypotension • splenic rupture • splenomegaly • vision loss Medication: — Clinical Procedure: Case Report Specialty: Oncology Objective: Unusual clinical course Background: Rituximab is a therapeutic monoclonal antibody that is used for many different lymphomas. Post-marketing surveillance has revealed that the risk of fatal reaction with rituximab use is extremely low. Splenic rupture and cytokine release syndrome are rare fatal adverse events related to the use of therapeutic monoclonal antibodies, especially in aggressive malignancies with high tumor burden. Case Report: A 55-year-old woman presented with abdominal pain and type B symptoms and was diagnosed with mantle cell lymphoma. Initial peripheral blood flow cytometry showed findings that mimicked features of chronic lymphocytic leukemia. Further treatment with rituximab led to catastrophic treatment complications that proved to be fatal for the patient. Conclusions: Severe cytokine release syndrome associated with biologics carries a very high morbidity and case fatality rate. With this case report we aim to present the diagnostic challenge with small B-cell neoplasms, especially mantle cell lymphoma and chronic lymphocytic lymphomas, and underscore the importance of thorough risk assessment for reactions prior to treatment initiation. PMID:26972227

  13. Monoclonal antibodies and neuroblastoma

    SciTech Connect

    Miraldi, F. )

    1989-10-01

    Several antineuroblastoma monoclonal antibodies (MoAbs) have been described and two have been used in radioimmunoimaging and radioimmunotherapy in patients. MoAb 3F8 is a murine IgG3 antibody specific for the ganglioside GD2. Radioiodine-labeled 3F8 has been shown to specifically target human neuroblastoma in patients, and radioimmunoimaging with this agent has provided consistently high uptakes with tumor-to-background ratios of greater than or equal to 10:1. Radioimmunotherapy has been attempted with both MoAb 3F8 and MoAb UJ13A, and although encouraging results have been obtained, dosimetry data and tissue dose response information for these agents is lacking, which impedes the development of such therapy. 124I, a positron emitter, can be used with 3F8 in positron emission tomography (PET) scanning to provide dosimetry information for radioimmunotherapy. The tumor radiation dose response from radiolabeled MoAb also can be followed with PET images with fluorodeoxyglucose (FDG) scanning of neuroblastoma tumors. Results to date indicate that radioimmunoimaging has clinical use in the diagnosis of neuroblastoma and the potential for radioimmunotherapy for this cancer remains high.48 references.

  14. A pretargeting system for tumor PET imaging and radioimmunotherapy.

    PubMed

    Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Frampas, Eric; Faivre-Chauvet, Alain; Rauscher, Aurore; Sharkey, Robert M; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2015-01-01

    Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed. PMID:25873896

  15. A pretargeting system for tumor PET imaging and radioimmunotherapy

    PubMed Central

    Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Frampas, Eric; Faivre-Chauvet, Alain; Rauscher, Aurore; Sharkey, Robert M.; Goldenberg, David M.; Chatal, Jean-François; Barbet, Jacques

    2015-01-01

    Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed. PMID:25873896

  16. Combination of cyclophosphamide, rituximab, and intratumoral CpG oligodeoxynucleotide successfully eradicates established B cell lymphoma.

    PubMed

    Betting, David J; Hurvitz, Sara A; Steward, Kristopher K; Yamada, Reiko E; Kafi, Kamran; van Rooijen, Nico; Timmerman, John M

    2012-09-01

    Rituximab plus chemotherapy is standard therapy for patients with non-Hodgkin B cell lymphoma, but often complete response or cure is not achieved. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) can improve antibody-dependent cellular cytotoxicity and adaptive antitumor immune responses. Using a syngeneic murine B cell lymphoma expressing human CD20 (38C13-huCD20), we previously demonstrated that rituximab plus intratumoral CpG, but not systemic CpG, could eradicate up to half of 7-day established 38C13-huCD20 tumors. However, larger 10-day established tumors could not be cured with this regimen. We thus hypothesized that cytoreduction with cyclophosphamide (Cy) before immunotherapy might permit eradication of these more advanced tumor burdens. Pretreatment with Cy resulted in tumor eradication from 83% of animals treated with rituximab/CpG, whereas Cy/CpG or Cy/rituximab treatments only cured 30% or 17%, respectively (P<0.005). Tumor eradication depended on natural killer cells, but not T cells, macrophages, or complement. Only mice treated with Cy/rituximab/CpG partially resisted rechallenge with tumor cells. Foxp3 Treg and CD11bGr1 myeloid suppressor cells persisted within lymphoid organs after therapy, possibly influencing the ability to establish adaptive tumor immunity. In conclusion, cytoreduction with Cy permitted the cure of large, established lymphomas not otherwise responsive to rituximab plus intratumoral CpG immunotherapy. PMID:22892450

  17. Early-onset neutropenia induced by rituximab in a patient with lupus nephritis and hemolytic anemia.

    PubMed

    Arroyo-Ávila, Mariangelí; Fred-Jiménez, Ruth M; Vilá, Luis M

    2015-01-01

    Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE) including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 10(9)/L) after the second weekly rituximab infusion (375 mg/m(2) weekly × 4) given for nephritis and hemolytic anemia. She also had early-onset thrombocytopenia after rituximab therapy. Both hematological disorders resolved 12 days after the fourth and final dose. This case, together with few others, suggests that early-onset neutropenia may occur during rituximab therapy. Even though rituximab-induced neutropenia seems to be transient, it may predispose SLE patients to severe complications such as infections. PMID:25767732

  18. Early-Onset Neutropenia Induced by Rituximab in a Patient with Lupus Nephritis and Hemolytic Anemia

    PubMed Central

    Arroyo-Ávila, Mariangelí; Fred-Jiménez, Ruth M.; Vilá, Luis M.

    2015-01-01

    Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE) including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 109/L) after the second weekly rituximab infusion (375 mg/m2 weekly × 4) given for nephritis and hemolytic anemia. She also had early-onset thrombocytopenia after rituximab therapy. Both hematological disorders resolved 12 days after the fourth and final dose. This case, together with few others, suggests that early-onset neutropenia may occur during rituximab therapy. Even though rituximab-induced neutropenia seems to be transient, it may predispose SLE patients to severe complications such as infections. PMID:25767732

  19. Use of Rituximab for Refractory Cytopenias Associated with Autoimmune Lymphoproliferative Syndrome (ALPS)

    PubMed Central

    Rao, V. Koneti; Price, Susan; Perkins, Katie; Aldridge, Patricia; Tretler, Jean; Davis, Joie; Dale, Janet K.; Gill, Fred; Hartman, Kip R.; Stork, Linda C.; Gnarra, David J.; Krishnamurti, Lakshmanan; Newburger, Peter E.; Puck, Jennifer; Fleisher, Thomas

    2009-01-01

    Background ALPS is a disorder of apoptosis resulting in accumulation of autoreactive lymphocytes, leading to marked lymphadenopathy, hepatosplenomegaly and multilineage cytopenias due to splenic sequestration and/or autoimmune destruction often presenting in childhood. We summarize our experience of rituximab use during the last 8 years in twelve patients, 9 children and 3 adults, out of 259 individuals with ALPS, belonging to 166 families currently enrolled in studies at the National Institutes of Health. Methods Refractory immune thrombocytopenia (platelet count <20,000) in 9 patients and autoimmune hemolytic anemia (AIHA) in 3 patients led to treatment with rituximab. Among them, 7 patients had undergone prior surgical splenectomy; 3 had significant splenomegaly; and 2 had no palpable spleen. Results In 7 out of 9 patients with ALPS and thrombocytopenia, rituximab therapy led to median response duration of 21months (range 14–36 months). In contrast, none of the 3 children treated with rituximab for AIHA responded. Noted toxicities included profound and prolonged hypogammaglobulinemia in 3 patients requiring replacement IVIG, total absence of antibody response to polysaccharide vaccines lasting up to 4 years after rituximab infusions in 1 patient and prolonged neutropenia in 1 patient. Conclusion Toxicities including hypogammaglobulinemia and neutropenia constitute an additional infection risk burden, especially in asplenic individuals, and may warrant avoidance of rituximab until other immunosuppressive medication options are exhausted. Long term follow up of ALPS patients with cytopenias after any treatment is necessary to determine relative risks and benefits. PMID:19214977

  20. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study

    PubMed Central

    Padmanabhan, Swaminathan; Chan, Geoffrey W.; Gupta, Ira V.; Lisby, Steen; Österborg, Anders

    2011-01-01

    Ofatumumab, the human CD20 monoclonal antibody that binds a distinct epitope from rituximab, has demonstrated clinical benefit as monotherapy for patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab (FA-ref) and patients refractory to fludarabine with bulky (> 5 cm) lymph nodes (BF-ref). To potentially gain insight into outcomes in patients previously treated with or refractory to rituximab, we performed an ad hoc retrospective analysis in the final 96 FA-ref and 111 BF-ref patients. There were 117 patients previously treated with rituximab (98 rituximab-refractory); 89 patients were rituximab-naive. For rituximab-treated, rituximab-refractory, and rituximab-naive patients, overall response rate was 43%, 44%, and 53%; median progression-free survival was 5.3, 5.5, and 5.6 months; and median overall survival was 15.5, 15.5, and 20.2 months. There were no significant differences in ofatumumab-related infusion reactions, or hematologic or infectious adverse events between subgroups. In summary, ofatumumab monotherapy was effective and well tolerated in patients with fludarabine-refractory chronic lymphocytic leukemia, including in patients with previous rituximab exposure. This trial was registered at www.clinicaltrials.gov as #NCT00349349. PMID:21856867

  1. Practical simplifications for radioimmunotherapy dosimetric models

    SciTech Connect

    Shen, S.; DeNardo, G.L.; O`Donnell, R.T.; Yuan, A.; DeNardo, D.A.; Macey, D.J.; DeNardo, S.J.

    1999-01-01

    Radiation dosimetry is potentially useful for assessment and prediction of efficacy and toxicity for radionuclide therapy. The usefulness of these dose estimates relies on the establishment of a dose-response model using accurate pharmacokinetic data and a radiation dosimetric model. Due to the complexity in radiation dose estimation, many practical simplifications have been introduced in the dosimetric modeling for clinical trials of radioimmunotherapy. Although research efforts are generally needed to improve the simplifications used at each stage of model development, practical simplifications are often possible for specific applications without significant consequences to the dose-response model. In the development of dosimetric methods for radioimmunotherapy, practical simplifications in the dosimetric models were introduced. This study evaluated the magnitude of uncertainty associated with practical simplifications for: (1) organ mass of the MIRD phantom; (2) radiation contribution from target alone; (3) interpolation of S value; (4) macroscopic tumor uniformity; and (5) fit of tumor pharmacokinetic data.

  2. Suppression of Rituximab-resistant B-cell lymphoma with a novel multi-component anti-CD20 mAb nanocluster

    PubMed Central

    Zhao, He; Sun, Yun; Zhao, Mengxin; Chen, Di; Zhu, Xiandi; Zhang, Li; Li, Bohua; Dai, Jianxin; Li, Wei

    2015-01-01

    Although the anti-CD20 antibody Rituximab has revolutionized the treatment of Non-Hodgkin Lymphoma (NHL), resistance to treatment still existed. Thus, strategies for suppressing Rituximab-resistant NHLs are urgently needed. Here, an anti-CD20 nanocluster (ACNC) is successfully constructed from its type I and type II mAb (Rituximab and 11B8). These distinct anti-CD20 mAbs are mass grafted to a short chain polymer (polyethylenimine). Compared with parental Rituximab and 11B8, the ACNC had a reduced “off-rate”. Importantly, ACNC efficiently inhibited Rituximab-resistant lymphomas in both disseminated and localized human NHL xenograft models. Further results revealed that ACNC is significantly potent in inducing caspase-dependent apoptosis and lysosome-mediated programmed cell death (PCD). This may help explain why ACNC is effective in suppressing rituximab-resistant lymphoma while Rituximab and 11B8 are not. Additionally, ACNC experienced low clearance from peripheral blood and high intratumor accumulation. This improved pharmacokinetics is attributed to the antibody-antigen reaction (active targeting) and enhanced permeability and retention (ERP) effect (passive targeting). This study suggested that ACNC might be a promising therapeutic agent for treatment of rituximab-resistant lymphomas. PMID:26284588

  3. Radioimmunotherapy of Cryptococcus neoformans spares bystander mammalian cells

    PubMed Central

    Bryan, Ruth A; Jiang, Zewei; Morgenstern, Alfred; Bruchertseifer, Frank; Casadevall, Arturo; Dadachova, Ekaterina

    2013-01-01

    Aim Previously, we showed that radioimmunotherapy (RIT) for cryptococcal infections using radioactively labeled antibodies recognizing the cryptococcal capsule reduced fungal burden and prolonged survival of mice infected with Cryptococcus neoformans. Here, we investigate the effects of RIT on bystander mammalian cells. Materials & methods Heat-killed C. neoformans bound to anticapsular antibodies, unlabeled or labeled with the β-emitter rhenium-188 (16.9-h half-life) or the α-emitter bismuth-213 (46-min half-life), was incubated with macrophage-like J774.16 cells or epithelial-like Chinese hamster ovary cells. Lactate dehydrogenase activity, crystal violet uptake, reduction of tetrazolium dye (2,3)-bis-(2-methoxy-4-nitro-5-sulfenyl)-(2H)-terazolium-5-carboxanilide and nitric oxide production were measured. Results The J774.16 and Chinese hamster ovary cells maintained membrane integrity, viability and metabolic activity following exposure to radiolabeled C. neoformans. Conclusion RIT of C. neoformans is a selective therapy with minimal effects on host cells and these results are consistent with observations that RIT-treated mice with cryptococcal infection lacked RIT-related pathological changes in lungs and brain tissues. PMID:24020737

  4. In vivo generator for radioimmunotherapy

    DOEpatents

    Mausner, Leonard F.; Srivastava, Suresh G.; Straub, Rita F.

    1988-01-01

    The present invention involves labeling monoclonal antibodies with intermediate half-life radionuclides which decay to much shorter half-life daughters with desirable high energy beta emissions. Since the daughter will be in equilibrium with the parent, it can exert an in-situ tumoricidal effect over a prolonged period in a localized fashion, essentially as an "in-vivo generator". This approach circumvents the inverse relationship between half-life and beta decay energy. Compartmental modeling was used to determine the relative distribution of dose from both parent and daughter nuclei in target and non-target tissues. Actual antibody biodistribution data have been used to fit realistic rate constants for a model containing tumor, blood, and non-tumor compartments. These rate constants were then used in a variety of simulations for two generator systems, Ba-128/Cs-128 (t.sub.1/2 =2.4d/3.6m) and Pd-112/Ag-112 (t.sub.1/2 =0.9d/192m). The results show that higher tumor/background dose ratios may be achievable by virtue of the rapid excretion of a chemically different daughter during the uptake and clearance phases. This modeling also quantitatively demonstrates the favorable impact on activity distribution of a faster monoclonal antibody tumor uptake, especially when the antibody is labeled with a radionuclide with a comparable half-life.

  5. In vivo generator for radioimmunotherapy

    DOEpatents

    Mausner, Leonard F.; Srivastava, Suresh G.; Straub, Rita F.

    1988-11-01

    The present invention involves labeling monoclonal antibodies with intermediate half-life radionuclides which decay to much shorter half-life daughters with desirable high energy beta emissions. Since the daughter will be in equilibrium with the parent, it can exert an in-situ tumoricidal effect over a prolonged period in a localized fashion, essentially as an "in-vivo generator". This approach circumvents the inverse relationship between half-life and beta decay energy. Compartmental modeling was used to determine the relative distribution of dose from both parent and daughter nuclei in target and non-target tissues. Actual antibody biodistribution data have been used to fit realistic rate constants for a model containing tumor, blood, and non-tumor compartments. These rate constants were then used in a variety of simulations for two generator systems, Ba-128/Cs-128 (t.sub.1/2 =2.4d/3.6m) and Pd-112/Ag-112 (t.sub.1/2 =0.9d/192m). The results show that higher tumor/background dose ratios may be achievable by virtue of the rapid excretion of a chemically different daughter during the uptake and clearance phases. This modeling also quantitatively demonstrates the favorable impact on activity distribution of a faster monoclonal antibody tumor uptake, especially when the antibody is labeled with a radionuclide with a comparable half-life.

  6. Sustained Elite Suppression of Replication Competent HIV-1 in a Patient Treated With Rituximab Based Chemotherapy

    PubMed Central

    Gaillard, Stephanie; Dinoso, Jason B.; Marsh, Julia A.; DeZern, Amy E.; O’Connell, Karen A; Spivak, Adam M.; Alwood, Karla; Durand, Christine M.; Ambinder, Richard F.; Blankson, Joel N.

    2011-01-01

    The mechanism of elite control of HIV-1 replication is not fully understood. While immunosuppression due to rituximab based chemotherapy has been associated with increased replication of HBV, CMV, and HIV-1, control of replication-competent HIV-1 was maintained in an elite controller/suppressor treated with a regimen that included vincristine, cyclophosphamide, prednisone, four rounds of plasmapheresis and ten cycles of rituximab. The data suggests that de-novo antibody responses do not play a significant role in the control of viral replication in these patients. PMID:21550842

  7. Recurrent inflammatory pseudotumor of the jaw with perineural intracranial invasion demonstrating sustained response to Rituximab.

    PubMed

    Garcia, Bryan A; Tinsley, Sarah; Schellenberger, Thomas; Bobustuc, George C

    2012-12-01

    Corticosteroids are the mainstay of treatment of inflammatory pseudotumor (IPT) of the head and neck; however, involvement of the skull base and mandible can be unresponsive to steroids and require surgical resection. IPT is known to usually contain a CD20+ lymphocyte subgroup. Rituximab, a chimeric anti-CD20 antibody, has been successfully utilized in the treatment of other CD20+ diseases, including the similar idiopathic orbital inflammatory disease. This is the first report to describe successful treatment with Rituximab of a recurrent IPT of the mandible with trigeminal spread and leptomeningeal involvement with clinical and radiologic evidence demonstrating a sustained response to therapy. PMID:22161155

  8. Pretargeted molecular imaging and radioimmunotherapy.

    PubMed

    Goldenberg, David M; Chang, Chien-Hsing; Rossi, Edmund A; J, William; McBride; Sharkey, Robert M

    2012-01-01

    Pretargeting is a multi-step process that first has an unlabeled bispecific antibody (bsMAb) localize within a tumor by virtue of its anti-tumor binding site(s) before administering a small, fast-clearing radiolabeled compound that then attaches to the other portion of the bsMAb. The compound's rapid clearance significantly reduces radiation exposure outside of the tumor and its small size permits speedy delivery to the tumor, creating excellent tumor/nontumor ratios in less than 1 hour. Haptens that bind to an anti-hapten antibody, biotin that binds to streptavidin, or an oligonucleotide binding to a complementary oligonucleotide sequence have all been radiolabeled for use by pretargeting. This review will focus on a highly flexible anti-hapten bsMAb platform that has been used to target a variety of radionuclides to image (SPECT and PET) as well as treat tumors. PMID:22737190

  9. Pretargeted Molecular Imaging and Radioimmunotherapy

    PubMed Central

    Goldenberg, David M.; Chang, Chien-Hsing; Rossi, Edmund A.; J, William; McBride; Sharkey, Robert M.

    2012-01-01

    Pretargeting is a multi-step process that first has an unlabeled bispecific antibody (bsMAb) localize within a tumor by virtue of its anti-tumor binding site(s) before administering a small, fast-clearing radiolabeled compound that then attaches to the other portion of the bsMAb. The compound's rapid clearance significantly reduces radiation exposure outside of the tumor and its small size permits speedy delivery to the tumor, creating excellent tumor/nontumor ratios in less than 1 hour. Haptens that bind to an anti-hapten antibody, biotin that binds to streptavidin, or an oligonucleotide binding to a complementary oligonucleotide sequence have all been radiolabeled for use by pretargeting. This review will focus on a highly flexible anti-hapten bsMAb platform that has been used to target a variety of radionuclides to image (SPECT and PET) as well as treat tumors. PMID:22737190

  10. Rituximab's new therapeutic target: the podocyte actin cytoskeleton.

    PubMed

    Chan, Andrew C

    2011-06-01

    Therapeutic off-target activities are well recognized for small-molecule drugs. In contrast, monoclonal antibodies (mAbs) traditionally are believed to act specifically and lack off-target therapeutic effects. In this issue of Science Translational Medicine, Fornoni et al. show therapeutic benefit, through an off-target-mediated mechanism, of the mAb drug rituximab in recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation. These data shed new light on FSGS pathogenesis and suggest new therapeutic interventions for proteinuric diseases. PMID:21632983

  11. Evaluation of chelating agents for radioimmunotherapy with scandium-47

    SciTech Connect

    Mausner, L.F.; Joshi, V.; Kolsky, K.L.

    1995-05-01

    Sc-47 has attractive properties [t{1/2} 3.35d, {beta}{sub max}:441 keV (68%), 601 keV (32%); {gamma} 159.4 keV (68%)] for radioimmunotherapy. Sc also displays favorable coordination chemistry for chelation attachment to antibodies. Due to chemical similarities to In and Y we have tested ligands with Sc-47 originally developed for use with In-111 or Y-90. The Scl-47 was produced with a fast neutron reaction Ti-47 (n,p). The radiochemical separation used cation exchange (AG-MP50) loaded with a 2% H{sub 2}O{sub 2} - 1 M H{sub 2}SO{sub 4} solution, followed by elution of Sc-47 with a 1 M NH{sub 4}{sub 2}SO{sub 4}/0.25 M H{sub 2}SO{sub 4} solution. Further separation and conversion of Sc to chloride form is achieved with a Chelex 100 column. No traces of Ti or Fe could be detected by spectrophotometric assay. Anti-CEA F(ab{prime});{sub 2} antibody conjugates of the following chelates were used for labeling studies: 4-isothiocyanato-cyclohexyl EDTA (4-ICE), N-hydroxysuccinimide ester of DOTA {l_angle}DOTA NHS{r_angle}, 2-{l_angle}p-SCN-Bz{r_angle}-6 methyl DTPA {l_angle}1B4MDTPA{r_angle} and conventional DTPA dianhydride. Labeling yields with Sc-47 were, 4-ICE 80%, DOTAQ-NHS 64%, 1B4MDTPA 98% and DTPA 62%. Serum stability of these preparations was essentially 100% out to 48 h except for DTPA (61%). The biodistribution {l_angle}% ID/g{r_angle} of these conjugates in human tumor xenografted nude mice {l_angle}LS-174% cells{r_angle} was compared. 4-ICE, DOTA-NHS and 1B4M-DTPA(15.4, 7.0, 7.0) but liver uptake was somewhat higher for DOTA-NHS than 4-ICE or 1B4M-DTPA (9.4, 5.8, 5.6). Generally faster whole body clearance for 1B4M-DTPA led to somewhat better tumor to organ ratios by 48 h. The poor stability of DTPA conjugate was evident with poor tumor uptake (12.4), high kidney (14.8), liver (17.1) and bone (3.6). We conclude that ligands which perform better with In-111 and Y-90 also give stable Sc-47 conjugates and their biodistributions are favorable for radioimmunotherapy.

  12. Vulvovaginal pyoderma gangrenosum secondary to rituximab therapy.

    PubMed

    Dixit, Shreya; Selva-Nayagam, Priya; Hamann, Ian; Fischer, Gayle

    2015-01-01

    Rituximab is being used increasingly for the treatment of B-cell malignancies and nonmalignant conditions. Pyoderma gangrenosum is a rare neutrophilic dermatosis, which can be either idiopathic or associated with underlying systemic inflammatory conditions. We present a series of 4 patients who presented with ulcerative pyoderma gangrenosum in the vulvovaginal area after treatment with rituximab. PMID:24769650

  13. Changes in B and T lymphocytes and chemokines with rituximab treatment in multiple sclerosis

    PubMed Central

    Piccio, Laura; Naismith, Robert T.; Trinkaus, Kathryn; Klein, Robyn S.; Parks, Becky J.; Lyons, Jeri A.; Cross, Anne H.

    2010-01-01

    Background B cells are implicated in the pathogenesis of multiple sclerosis (MS). A beneficial effect of B cell depletion using rituximab has been shown, but the complete mechanism of action for this drug is unclear. Objective To determine the relationship between T cells, B cells, and changes in CSF chemokines with rituximab, a monoclonal antibody that targets CD20. Design Phase II trial of rituximab as an add-on therapy. Setting The John L. Multiple Sclerosis Center, Washington University, St. Louis, Missouri. Patients Thirty relapsing-remitting MS subjects with clinical and MRI activity despite treatment with an immunomodulatory drug received four weekly doses of 375mg/m2 rituximab. Main Outcome Measures Lumbar puncture was performed before and after rituximab infusions in 26 subjects. CSF B and T lymphocytes were enumerated by flow cytometry, and chemoattractants were measured by ELISA. Results After rituximab administration, CSF B cells were decreased or undetectable in all subjects and CSF T cells were reduced in 81% of subjects. The mean reduction in CSF cellularity was 95% for B cells and 50% for T cells. After rituximab infusion, CSF CXCL13 and CCL19 decreased (P= 0.002, P=0.03, respectively). The proportional decline in CSF T cells correlated with the proportional decrease in CXCL13 (r=0.45;P=0.03), suggesting a possible relationship. CSF IgG index, IgG concentration, and oligoclonal band number were unchanged following treatment. Conclusions B cells are critical for T cell trafficking into the CNS in MS patients, and may alter T cell trafficking by influencing chemokine production within the CNS. PMID:20558389

  14. Practical considerations on the use of rituximab in autoimmune neurological disorders

    PubMed Central

    Kosmidis, Mixalis L.; Dalakas, Marinos C.

    2010-01-01

    Rituximab (Mabthera, Rituxan) is a chimeric human/murine monoclonal antibody against CD-20 surface antigen expressed on B-cells. Rituximab, by causing B-cell depletion, appears to be effective in several autoimmune disorders; it has been approved for rheumatoid arthritis and is a promising new agent in the treatment of several autoimmune neurological disorders. A controlled study in patients with relapsing remitting multiple sclerosis has shown that rituximab significantly reduces the number of new MRI lesions and improves clinical outcome; it also showed some promise in a subset of patients with primary progressive MS. The drug is also effective in a number of patients with Devic’s disease, myasthenia gravis, autoimmune neuropathies, and inflammatory myopathies. The apparent effectiveness of rituximab has moved B-cells into the center stage of clinical and laboratory investigation of autoimmune neurological disorders. We review the evidence-based effectiveness of rituximab in neurological disorders based on controlled trials and anecdotal reports, including our own experience, and address the immunobiology of B-cells in autoimmune central nervous system (CNS) and peripheral nervous system (PNS) disorders. In addition, we provide practical guidelines on how best to use this drug in clinical practice and highlight its potential toxicity. PMID:21179602

  15. Rituximab as Single Agent in Primary MALT Lymphoma of the Ocular Adnexa

    PubMed Central

    Annibali, Ombretta; Chiodi, Francesca; Sarlo, Chiara; Cortes, Magdalena; Quaranta-Leoni, Francesco M.; Quattrocchi, Carlo; Bianchi, Antonella; Bonini, Stefano; Avvisati, Giuseppe

    2015-01-01

    Ocular Adnexal Lymphomas are the first cause of primary ocular malignancies, and among them the most common are MALT Ocular Adnexal Lymphomas. Recently systemic immunotherapy with anti-CD20 monoclonal antibody has been investigated as first-line treatment; however, the optimal management for MALT Ocular Adnexal Lymphomas is still unknown. The present study evaluated retrospectively the outcome of seven consecutive patients with primary MALT Ocular Adnexal Lymphomas, of whom six were treated with single agent Rituximab. All patients received 6 cycles of Rituximab 375 mg/mq every 3 weeks intravenously. The overall response rate was 100%; four patients (67%) achieved a Complete Remission, and two (33%) achieved a partial response. In four patients an additional Rituximab maintenance every 2-3 months was given for two years. After a median follow-up of 29 months (range 8–34), no recurrences were observed, without of therapy- or disease-related severe adverse events. None of the patients needed additional radiotherapy or other treatments. Rituximab as a single agent is highly effective and tolerable in first-line treatment of primary MALT Ocular adnexal Lymphomas. Furthermore, durable responses are achievable with the same-agent maintenance. Rituximab can be considered the agent of choice in the management of an indolent disease in whom the “quality of life” matter is of primary importance. PMID:26425558

  16. Rituximab for Non-Hodgkin’s Lymphoma: A Story of Rapid Success in Translation

    PubMed Central

    Harrison, Andrew M.; Thalji, Nassir M.; Greenberg, Alexandra J.; Tapia, Carmen J.; Windebank, Anthony J.

    2014-01-01

    Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non-Hodgkin’s lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation. PMID:24528902

  17. The feasibility of radioimmunotherapy of head and neck cancer.

    PubMed

    Gerretsen, M; Quak, J J; Brakenhoff, R H; Snow, G B; van Dongen, G A

    1994-01-01

    Since the introduction of the hybridoma technology by Kohler and Milstein (Nature 1975, 256, 495-497), tremendous effort has been put in the realisation of Ehrlich's concept of the magic bullet, which was proposed as early as the beginning of the century. The first clinical studies for radioimmunoscintigraphy (RIS) and radioimmunotherapy (RIT) with radiolabelled antibodies were undertaken in the early 1980s. Since then, RIS has been performed on thousands of patients with various types of malignancies, like colon carcinoma, lung carcinoma, breast carcinoma, neuroblastoma, T-cell lymphoma and ovarian carcinoma. In addition, a substantial number of therapy trials with radiolabelled antibodies have been performed. The developments for head and neck squamous cell carcinoma (HNSCC) have only recently been able to catch up with these events to some extent. One of the main reasons for this slow progress has been the lack of monoclonal antibodies (Mab) with specificity for HNSCC. Although there are as yet no real tumour specific antigens known for HNSCC, which also holds true for the majority of malignancies arising from other tissues, we now have the availability of a number of Mab with high specificity for HNSCC and with a very restricted reaction pattern with normal tissues. Labelled with 131I, these Mab have been shown to be highly capable to localise in HNSCC xenografts in nude mice. Based on these promising data, patient studies with one of these Mab, designated Mab E48, labelled with 99mTc, were started to evaluate the feasibility of RIS in patients with head and neck cancer.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8032305

  18. Radioimmunotherapy: Development of an effective approach. Annual report, 1991

    SciTech Connect

    DeNardo, S.J.

    1991-12-31

    We plan to extend our success in treating B cell malignancies with {sup 131}I labeled Lym-1 by a major effort in therapy with {sup 67}Cu Lym-1. Yttrium-90 labeled by a macrocycle, DOTA will be studied in patients as a continuation of the {sup 111}In-BAD (DOTA) Lym-1 studies. Excellent images and pharmacokinetics of the {sup 111}In-BAD(DOTA)-Lym-1 studies. Lymphomas and related diseases represent a special case for radioimmunotherapy because of their documented radiosensitivity and immunodeficiency, and thus offer a unique opportunity to conduct therapeutic feasibility studies in a responsive human model. Using marine and chimeric L6 and other MoAb to breast cancer, we have applied the strategies that were developed in taking Lym-1 antibody from the bench to the patient. We have examined a number of monoclonal antibodies for treatment of breast cancer and chose chimeric L6 for prototype studies because of certain characteristics. The chemistry of attachment of conjugates to antibodies and their impact on immunological targeting biological activities (cytotoxicity), metabolic fate, and therapeutic index will continue to be a major strength and function of this program. This grant has supported the conception, synthesis, and development of the first macrocylic, bifunctional chelating agent TETA (6-p-nitrobenzyl-1,4,8,11-tetraazatetradecane-N,N{prime},N{double_prime}, N{prime}{double_prime}-tetraacetic acid and its derivatives, including Lym-1-2IT-BAT), for use in Cu-67-based radioimmunodiagnosis and therapy. This work has led to the further development of several new macrocylic bifunctional chelating agents for copper, indium, yttrium and other metals. In addition, successful Cu-67 labelings of Lym-1-2IT-BAT for human radiopharmaceutical have shown patient pharmacokinetics of {sup 67}Cu-BAT(TETA)-Lym-1 with promising therapeutic dosimetry.

  19. A review of the current use of rituximab in autoimmune diseases.

    PubMed

    Gürcan, Hakan M; Keskin, Derin B; Stern, Joel N H; Nitzberg, Matthew A; Shekhani, Haris; Ahmed, A Razzaque

    2009-01-01

    Rituximab is a human/murine chimeric monoclonal antibody primarily used for treating non-Hodgkin's B-cell lymphoma. Recently it has also been used in the treatment of several autoimmune diseases. A literature review was conducted to determine the efficacy of rituximab in the treatment of some of these autoimmune diseases. Multiple mechanisms proposed for the rituximab mediated B cell depletion are also discussed. The efficacy of rituximab is well-established and it is FDA approved for treatment of Rheumatoid arthritis. In this review, data on the use of rituximab is presented from 92 studies involving 1197 patients with the following diseases: systemic lupus erythematosus, idiopathic thrombocytopenic purpura, anti-neutrophil cytoplasmic antibody associated vasculitis, Grave's disease, autoimmune hemolytic anemia, pemphigus vulgaris, hemophilia A, cold agglutinin disease, Sjogren's syndrome, graft vs. host disease, thrombotic thrombocytopenic purpura, cryoglobulinemia, IgM mediated neuropathy, multiple sclerosis, neuromyelitis optica, idiopathic membranous nephropathy, dermatomyositis, and opsoclonus myoclonus. The efficacy varies among different autoimmune diseases. The cumulative data would suggest that in the vast majority of studies in this review, RTX has a beneficial role in their treatment. While rituximab is very effective in the depletion of B cells, current research suggests it may also influence other cells of the immune system by re-establishing immune homeostasis and tolerance. The safety profile of RTX reveals that most reactions are infusion related. In patients with autoimmune diseases the incidence of serious and severe side effects is low. Systemic infection still remains a major concern and may result in death. PMID:19000786

  20. Analysis of the effectiveness and safety of rituximab in patients with refractory lupus nephritis: a chart review.

    PubMed

    Contis, Anne; Vanquaethem, Helene; Truchetet, Marie-Elise; Couzi, Lionel; Rigothier, Claire; Richez, Christophe; Lazaro, Estibaliz; Duffau, Pierre

    2016-02-01

    Lupus nephritis is a life-threatening complication of systemic lupus erythematosus. The standard treatment for this condition, including corticosteroids and cyclophosphamide, results in a 70 % remission rate at 12 months, but it is also associated with significant morbidity. Rituximab, a chimeric anti-CD20 antibody, could be useful, given the central role of B cells in the pathogenesis of systemic lupus erythematosus. Case reports and retrospective series have reported that rituximab is effective for refractory lupus nephritis. However, the double-blind, placebo-controlled LUNAR trial failed to meet its end point. We studied clinical, biological, and immunological data on 17 patients who received rituximab as an induction treatment for refractory lupus nephritis at the University Hospital Center of Bordeaux. A complete treatment response was defined as a normal serum creatinine with inactive urinary sediment and 24-h urinary albumin <0.5 g and a partial response (PR) as a >50 % improvement in all of the renal parameters that were abnormal at baseline, with no deterioration in any parameter. Seventeen patients received rituximab as induction treatment for lupus nephritis refractory to standard treatment by cyclophosphamide. After a follow-up of 12 months, complete or partial renal remission was achieved in 53 % patients. Rituximab therapy resulted in a significant improvement in proteinuria and steroid dose tapering in all patients. Rituximab should be considered as a treatment option for refractory lupus glomerulonephritis. PMID:26762196

  1. Compartmental Intrathecal Radioimmunotherapy: Results for Treatment for Metastatic CNS Neuroblastoma

    PubMed Central

    Kramer, Kim; Kushner, Brian H.; Modak, Shakeel; Pandit-Taskar, Neeta; Smith-Jones, Peter; Zanzonico, Pat; Humm, John L.; Xu, Hong; Wolden, Suzanne L.; Souweidane, Mark M.; Larson, Steven M.; Cheung, Nai-Kong V.

    2012-01-01

    Innovation in the management of brain metastases is needed. We evaluated the addition of compartmental intrathecal antibody-based radioimmunotherapy (cRIT) in patients with recurrent metastatic central nervous system (CNS) neuroblastoma following surgery, craniospinal irradiation, and chemotherapy. 21 patients treated for recurrent neuroblastoma metastatic to the CNS received a cRIT-containing salvage regimen incorporating intrathecal 131I-monoclonal antibodies (MoAbs) targeting GD2 or B7H3 following surgery and radiation. Most patients also received outpatient craniospinal irradiation, 3F8/GMCSF immunotherapy, 13-cis-retinoic acid and oral temozolomide for systemic control. Seventeen of 21 cRIT-salvage patients are alive 7-74 months (median 33) since CNS relapse, with all 17 remaining free of CNS neuroblastoma. One patient died of infection at 22 months with no evidence of disease at autopsy, and one of lung and bone marrow metastases at 15 months, and one of progressive bone marrow disease at 30 months. The cRIT-salvage regimen was well tolerated, notable for myelosuppression minimized by stem cell support (n=5), and biochemical hypothyroidism (n=5). One patient with a 7-year history of metastatic neuroblastoma is in remission from MLL-associated secondary leukemia. This is significantly improved to published results with non-cRIT based where relapsed CNS NB has a median time to death of approximately 6 months. The cRIT-salvage regimen for CNS metastases was well tolerated by young patients, despite their prior history of intensive cytotoxic therapies. It has the potential to increase survival with better than expected quality of life. PMID:19890606

  2. Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high response rates and durable remissions in patients with previously treated B-cell lymphoma.

    PubMed

    Gordon, Leo I; Witzig, Thomas; Molina, Arturo; Czuczman, Myron; Emmanouilides, Christos; Joyce, Robin; Vo, Katie; Theuer, Charles; Pohlman, Brad; Bartlett, Nancy; Wiseman, Greg; Darif, Mohamed; White, Christine

    2004-09-01

    We report updated time-to-event variables of a phase III randomized study comparing yttrium 90-labeled ibritumomab with rituximab standard therapy in 143 rituximab-naive patients with relapsed or refractory low-grade, follicular, or transformed CD20+ non-Hodgkin's lymphoma (NHL). Most patients (79%) had follicular lymphoma. Patients were randomized to receive a single intravenous (I.V.) dose of 90Y ibritumomab tiuxetan 0.4 mCi/kg (n = 73) or rituximab 375 mg/m2 I.V. weekly for 4 doses (n = 70). The radioimmunotherapy group was pretreated with 2 rituximab doses (250 mg/m2) to improve biodistribution and one dose of Indium 111-labeled ibritumomab tiuxetan for imaging. The overall response rate was 80% versus 56% (P = 0.002) and complete response (CR)/CR unconfirmed (CRu) rates were 34% for 90Y ibritumomab tiuxetan versus 20% for rituximab. With a median follow-up of 44 months, the data are mature as all ongoing patients in both groups exceeded the median Kaplan-Meier estimated time to progression (TTP), duration of response (DR), and time to next therapy. Although this study was not powered to detect differences in time-to-event variables, the results from this randomized trial demonstrate trends toward longer median TTP (15 vs. 10.2 months; P = 0.07), DR (16.7 vs. 11.2 months; P = 0.44) and time to next therapy (21.1 vs. 13.8 months; P = 0.27) in follicular NHL patients treated with 90Y ibritumomab tiuxetan compared with the rituximab control arm. In patients achieving a CR/CRu, the median TTP was 24.7 months for patients treated with 90Y ibritumomab tiuxetan compared with 13.2 months for rituximab-treated patients (P = 0.41), and ongoing responses of > 5 years have been observed. These results confirm that 90Y ibritumomab tiuxetan produces high response rates and durable remissions in patients with previously treated low-grade, follicular, and transformed NHL. PMID:15453924

  3. Four cases of rituximab-associated melanoma.

    PubMed

    Velter, Charles; Pagès, Cécile; Schneider, Pierre; Osio, Amélie; Brice, Pauline; Lebbé, Céleste

    2014-08-01

    Biological agents have transformed the management of inflammatory and proliferative disorders. Safety issues have been raised, particularly the increased risk of opportunistic infections and secondary cancers. We report four cases of melanoma worsening or occurring after rituximab treatment for associated B-cell lymphoma, and discuss the accountability of the molecule in this process. In three cases, melanoma was diagnosed before or at the same time as a B-cell lymphoma treated with rituximab associated with chemotherapy and we observed rapid metastatic progression. In the last case, melanoma appeared after 5 years treatment with rituximab for a follicular lymphoma. Although it is premature to conclude on the role of rituximab in melanoma, careful follow-up and registration of such cases are important to gain further insight on this topic. PMID:24743053

  4. The potential of radioimmunotherapy as a new hope for HIV patients

    PubMed Central

    Tsukrov, Dina; Dadachova, Ekaterina

    2014-01-01

    HIV/AIDS remains an enormous public health burden. Advances in anti-retroviral therapy (ART) have greatly reduced mortality and morbidity but HIV remains incurable, with patients suffering numerous disease- and treatment-related side effects. Any curative strategy for HIV must selectively eliminate existing infected cells. Radioimmunotherapy (RIT) is an established clinical modality in cancer treatment and has been shown to be effective in multiple infectious diseases models. We have recently demonstrated that RIT using a gp41-targeting antibody was effective and safe in eliminating HIV-infected cells in vivo (in mice), in vitro, and ex vivo in cells from HIV patients treated with ART. In addition, there is strong evidence that this radiolabeled antibody can eliminate HIV infected cells across the blood brain barrier. We consider RIT to be the most promising backbone strategy for HIV eradication. PMID:24734906

  5. A Transition Metal Complex (Venus Flytrap Cluster) for Radioimmunodetection and Radioimmunotherapy

    NASA Astrophysics Data System (ADS)

    Paxton, Raymond J.; Beatty, Barbara G.; Hawthorne, M. Frederick; Varadarajan, Aravamuthan; Williams, Lawrence E.; Curtis, Frederick L.; Knobler, Carolyn B.; Beatty, J. David; Shiveley, John E.

    1991-04-01

    A novel transition metal complex, Venus flytrap cluster (VFC), is described for the preparation of radiolabeled antibodies. VFC contained 57Co, which was held tightly between the faces of two covalently bridged carborane ligands by cluster bonding of the metal with appropriate ligand orbitals. Anti-carcinoembryonic antigen monoclonal antibody T84.66 was conjugated to 57Co-VFC with full retention of immunological activity. Biodistribution studies in nude mice bearing carcinoembryonic antigen-producing tumors showed excellent tumor localization of 57Co-VFC-T84.66. The accumulation of radionuclide in normal liver was low and independent of dose, which may reflect the stability of the radionuclide complex. These results presage the use of VFC systems for binding transition metals that are clinically useful for radio-immunodiagnosis and radioimmunotherapy.

  6. A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy

    SciTech Connect

    Paxton, R.J.; Curtis, F.L.; Shively, J.E. ); Beatty, B.G.; Williams, L.E.; Beatty, J.D. ); Hawthorne, M.F.; Varadarajan, A.; Knobler, C.B. )

    1991-04-15

    A novel transition metal complex, Venus flytrap cluster (VFC), is described for the preparation of radiolabeled antibodies. VFC contained {sup 57}Co, which was held tightly between the faces of two covalently bridged carborane ligands by cluster bonding of the metal with appropriate ligand orbitals. Anti-carcinoembryonic antigen monoclonal antibody T84,66 was conjugated to {sup 57}Co-VFC with full retention of immunological activity. Biodistribution studies in nude mice bearing carcinoembryonic antigen-producing tumors showed excellent tumor localization of {sup 57}Co-VFC-T84.66. The accumulation of radionuclide in normal liver was low and independent of dose, which may reflect the stability of the radionuclide complex. These results presage the use of VFC systems for binding transition metals that are clinically useful for radioimmunodiagnosis and radioimmunotherapy.

  7. Rituximab for troublesome cases of childhood nephrotic syndrome

    PubMed Central

    Safdar, Osama Y; Aboualhameael, Adila; Kari, Jameela A

    2014-01-01

    Nephrotic syndrome (NS) is the most common glomerular disease of childhood. Steroid-dependent and steroid-resistant nephrotic syndrome present challenges in their pharmaceutical management; patients may need several immunosuppressive medication for optimum control, each of which medication has its own safety profile. Rituximab (RTX) is a monoclonal antibody that targets B cells and has been used successfully for management of lymphoma and rheumatoid arthritis. Recent clinical studies showed that rituximab may be an efficacious and safe alternative for the treatment of complicated nephrotic syndrome. In this review article, we aim to review the efficacy and safety of RTX therapy in nephrotic syndrome. We reviewed the literature pertaining to this topic by searching for relevant studies on PubMed and Medline using specific keywords. The initial search yielded 452 articles. These articles were then examined to ensure their relevance to the topic of research. We focused on multicenter randomized controlled trials with relatively large numbers of patients. A total of 29 articles were finally identified and will be summarized in this review. The majority of clinical studies of RTX in complicated pediatric NS showed that rituximab is effective in approximately 80% of patients with steroid-dependent NS, as it decreases the number of relapses and steroid dosage. However, RTX is less effective at achieving remission in steroid-resistant NS. RTX use was generally safe, and most side effects were transient and infusion-related. More randomized, double-blinded clinical studies are needed to assess the role of RTX in children with nephrotic syndrome. PMID:25512892

  8. Orthotopic xenografts of human melanoma and colonic and ovarian carcinoma in sheep to evaluate radioimmunotherapy.

    PubMed Central

    Turner, J. H.; Rose, A. H.; Glancy, R. J.; Penhale, W. J.

    1998-01-01

    Extrapolation to humans from experimental radioimmunotherapy in nude mouse xenograft models is confounded by large relative tumour size and small volume of distribution in mice allowing tumour uptake of radiolabelled antibodies unattainable in patients. Our large animal model of human tumours in cyclosporin-immunosuppressed sheep demonstrated tumour uptake of targeted radiolabelled monoclonal antibodies comparable with uptakes reported in clinical trials. Sheep immunosuppression with daily intravenous cyclosporin augmented by oral ketoconazole maintained trough blood levels of cyclosporin within the range 1000-1500 ng ml(-1). Human tumour cells were transplanted orthotopically by inoculation of 10(7) cells: SKMEL melanoma subcutaneously; LS174T and HT29 colon carcinoma into bowel, peritoneum and liver; and JAM ovarian carcinoma into ovary and peritoneum. Tumour xenografts grew at all sites within 3 weeks of inoculation, preserving characteristic morphology without evidence of necrosis or host rejection. Lymphatic metastasis was demonstrated in regional nodes draining xenografts of melanoma and ovarian carcinoma. Colonic LS1 74T xenografts produced mucin and carcinoembryonic antigen (CEA). The anti-CEA IgG1 monoclonal antibody A5B7 was radiolabelled with iodine-131 and administered intravenously to sheep. Peak uptake at 5 days in orthotopic human tumour transplants in gut was 0.027% DI g(-1) (percentage of injected dose per gram) and 0.034% DI g(-1) in hepatic metastases with tumour to blood ratios of 2-2.5. Non-specific tumour uptake in melanoma was 0.003% DI g(-1). Uptake of radiolabelled monoclonal antibody in human tumours in our large animal model is comparable with that observed in patients and may be more realistic than nude mice xenografts for prediction of clinical efficacy of radioimmunotherapy. Images Figure 1 Figure 2 Figure 3 PMID:9716032

  9. False Positive B-Cells Crossmatch after Prior Rituximab Exposure of the Kidney Donor

    PubMed Central

    Desoutter, Judith; Apithy, Marie-Joëlle; Bartczak, Ségolène; Guillaume, Nicolas

    2016-01-01

    Crossmatching is essential prior to kidney transplantation to confirm compatibility between the donor and the recipient, particularly to prevent acute antibody-mediated rejection. An unexpected positive crossmatch may be obtained in recipients with an autoimmune disease or preexisting antibodies not detected by single-antigen bead array due to complement interference or who have been previously treated by desensitization protocols such as rituximab, antithymocyte globulin, or intravenous immunoglobulins. We report donor and recipient investigations that revealed unexpected positive B-cells crossmatch, probably due to donor cells, as the donor had received rituximab therapy shortly before organ harvesting, in a context of severe idiopathic thrombocytopenic purpura. We consequently detected unexpected Class II IgG complement-dependent cytotoxicity for all sera tested. Other laboratory investigations failed to elucidate the reasons for this recipient-related positivity.

  10. Immunreconstitution and Infectious Complications After Rituximab Treatment in Children and Adolescents: What Do We Know and What Can We Learn from Adults?

    PubMed Central

    Worch, Jennifer; Makarova, Olga; Burkhardt, Birgit

    2015-01-01

    Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections. The kinetic of B-cell recovery is influenced by the concomitant chemotherapy and the underlying disease. Intensive B-NHL treatment such as high-dose chemotherapy followed by rituximab bears a risk for prolonged hypogammaglobulinemia. Overall transient alteration of immune reconstitution and infections after rituximab treatment are acceptable for children and adolescent without significant differences compared to adults. However, age related disparities in the kinetic of immune reconstitution and the definitive role of rituximab in the treatment for children and adolescents with B-cell malignancies need to be evaluated in prospective controlled clinical trials. PMID:25643241

  11. Immunreconstitution and infectious complications after rituximab treatment in children and adolescents: what do we know and what can we learn from adults?

    PubMed

    Worch, Jennifer; Makarova, Olga; Burkhardt, Birgit

    2015-01-01

    Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections. The kinetic of B-cell recovery is influenced by the concomitant chemotherapy and the underlying disease. Intensive B-NHL treatment such as high-dose chemotherapy followed by rituximab bears a risk for prolonged hypogammaglobulinemia. Overall transient alteration of immune reconstitution and infections after rituximab treatment are acceptable for children and adolescent without significant differences compared to adults. However, age related disparities in the kinetic of immune reconstitution and the definitive role of rituximab in the treatment for children and adolescents with B-cell malignancies need to be evaluated in prospective controlled clinical trials. PMID:25643241

  12. Fatal haemoptysis in a case of lymphomatoid granulomatosis treated with rituximab.

    PubMed

    Jaffre, S; Jardin, F; Dominique, S; Duet, E; Hubscher, Ph; Genevois, A; Corne, F; Bota, S; Nouvet, G; Thiberville, L

    2006-03-01

    Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive disease, which commonly involves the lungs but also the brain, kidneys, liver and skin. This report describes the case of a 33-yr-old female with an aggressive form of lymphoid granulomatosis treated with an anti-CD20 antibody. Dramatic radiological improvement was seen at the fourth week. However, the patient died at home 1 month after the last rituximab administration from a massive haemoptysis. PMID:16507866

  13. Successful therapy with rituximab of refractory acute humoral renal transplant rejection: a case report.

    PubMed

    Celik, A; Saglam, F; Cavdar, C; Sifil, A; Atila, K; Sarioglu, S; Bora, S; Gulay, H; Camsari, T

    2008-01-01

    Acute humoral rejection (AHR) is generally less responsive to conventional anti-rejection treatment with consequent allograft losses. Therapeutic options include antilymphocyte antibody (ATG), intravenous immunglobulin (IVIG), plasmapheresis, or immunoadsorption with protein A together with intensification of immunsuppression with a tacrolimus/mycophenolate mofetil combination. This report describes a transplant recipient who responded to rituximab therapy as treatment for steroid-, ATG-, IVIG-, and plasmapheresis-resistant AHR. PMID:18261611

  14. Successful Management of Refractory Dialysis Independent Wegener's Granulomatosis with Combination of Therapeutic Plasma Exchange and Rituximab.

    PubMed

    Malhotra, Sheetal; Dhawan, Hari Krishan; Sharma, Ratti Ram; Marwaha, Neelam; Sharma, Aman

    2016-06-01

    Wegeners granulomatosis (WG) is an autoimmune, antineutrophil cytoplasmic antibody mediated necrotizing vasculitis involving renal, and upper and lower respiratory systems. Treatment relies on a combination of immunosuppressive drugs and tapering regimen of glucocorticoids. Therapeutic plasma exchange (TPE) has been recognized as a second line treatment. We report the successful use of TPE in combination with rituximab in achieving remission in a patient with WG (dialysis independent) not responding to conventional therapy. PMID:27408429

  15. Rituximab in the treatment of autoimmune haemolytic anaemia.

    PubMed

    Rodrigo, Chaturaka; Rajapakse, Senaka; Gooneratne, Lallindra

    2015-05-01

    Rituximab is a B-cell depleting monoclonal antibody that is gaining popularity as an effective therapy for many autoimmune cytopenias. This article systematically evaluates its therapeutic efficacy in the treatment of different types of autoimmune haemolytic anaemia. We conclude that there is sufficient evidence to recommend it as a second line therapy for warm autoimmune haemolytic anaemia (wAIHA) either as monotherapy or combined therapy. Evidence from a single randomized controlled trial suggests that it may also be more efficacious as first line therapy in combination with steroids than steroids alone. A fewer number of studies have assessed its role in cold autoimmune haemolytic anaemia (cAIHA) and cold agglutinin disease (CAD) with success rates varying from 45-66%. In the absence of alternative definitive therapy, rituximab should be considered for patients with symptomatic CAD and significant haemolysis. Case reports of its efficacy in mixed autoimmune haemolytic anaemias are available but evidence from case series or larger cohorts are nonexistent. PMID:25139610

  16. Common variable immunodeficiency, immune thrombocytopenia, rituximab and splenectomy: important considerations.

    PubMed

    Arays, Ruta; Goyal, Sahil; Jordan, Kim M

    2016-08-01

    Common variable immunodeficiency (CVID) is readily considered in patients presenting with recurrent sino-pulmonary infections, however this disease has a broad range of clinical manifestations and diagnosis can be delayed by several years. We present the case of a 44-year-old postpartum female who presented with nausea, vomiting and abdominal distension. Four years prior, she was hospitalized for treatment of immune thrombocytopenia (ITP) with splenectomy and rituximab followed by two episodes of bacterial meningitis despite immunizations. The recurrent meningitis had been attributed to splenectomy and immunotherapy. During this hospitalization, extensive workup for gastrointestinal pathology was negative and she was diagnosed with intestinal pseudo-obstruction. Her hospital course was complicated by development of severe pseudomonas pneumonia, and subsequent immunoglobulin testing and impaired antibody response to vaccines were consistent with CVID. We review the clinical presentation of CVID, its association with autoimmune disease, and treatment implications, specifically the impact of rituximab therapy and splenectomy on immunoglobulin function and risk of serious infection. Intestinal pseudo-obstruction has been reported in children with CVID, but literature search failed to reveal similar presentation in adults. Physicians must consider the heterogeneous clinical manifestations of CVID to avoid delay in diagnosis and treatment. Institution of appropriate therapy with immunoglobulin replacement is important to decrease risk of serious infection. PMID:27276370

  17. Estimation of radiation absorbed doses to the red marrow in radioimmunotherapy

    SciTech Connect

    Macey, D.J.; DeNardo, S.J.; DeNardo, G.L.; DeNardo, D.A.; Sui Shen

    1995-02-01

    Myelotoxicity is the dose-limiting factor in radioimmunotherapy. Traditional methods most commonly used to estimate the radiation adsorbed dose to the bone marrow of patients consider contribution from radionuclide in the blood and/or total body. Targeted therapies, such as radioimmunotherapy, add a third potential source for radiation to the bone marrow because the radiolabeled targeting molecules can accumulate specifically on malignant target cells infiltrating the bone marrow. A non-invasive method for estimating the radiation absorbed dose to the red marrow of patients who have received radiolabeled monoclonal antibodies (MoAb) has been developed and explored. The method depends on determining the cumulated activity in three contributing sources: (1) marrow; (2) blood; and (3) total body. The novel aspect of this method for estimating marrow radiation dose is derivation of the radiation dose for the entire red marrow from radiation dose estimates obtained by detection of cumulated activity in three lumbar vertebrae using a gamma camera. Contributions to the marrow radiation dose form marrow, blood, and total body cumulated activity were determined for patients who received an I-131 labeled MoAb, Lym-1, that reacts with malignant B-lymphocytes of chronic lymphocytic leukemia and nonHodgkin`s lymphoma. Six patients were selected for illustrative purposes because their vertebrae were readily visualized on lumbar images. 32 refs., 6 figs., 1 tab.

  18. Rituximab Retreatment for Low-Tumor Burden Follicular Lymphoma

    Cancer.gov

    A summary of results from a randomized clinical trial of patients with low–tumor burden follicular lymphoma that compared maintenance therapy with rituximab versus retreatment with rituximab only when there was evidence of disease progression.

  19. Late Occurrence of PML in a Patient Treated for Lymphoma with Immunomodulatory Chemotherapies, Bendamustine, Rituximab, and Ibritumomab Tiuxetan

    PubMed Central

    Lane, Michael A.; Renga, Vijay; Pachner, Andrew R.; Cohen, Jeffrey A.

    2015-01-01

    PML caused by John Cunningham (JC) virus is a rare but an increasingly recognized entity. With the advent of newer immunomodulatory therapies with monoclonal antibodies, there is an increasing incidence of PML. Initially concern was restricted to patients treated for multiple sclerosis with natalizumab but more case reports are being reported during treatment for other conditions like Crohn's disease and lymphoma with agents such as rituximab. We report the case of a 66-year-old woman who developed PML a year after completion of therapy with rituximab, ibritumomab, and bendamustine. PMID:25705531

  20. High in Vitro Anti-Tumor Efficacy of Dimeric Rituximab/Saporin-S6 Immunotoxin

    PubMed Central

    Bortolotti, Massimo; Bolognesi, Andrea; Battelli, Maria Giulia; Polito, Letizia

    2016-01-01

    The anti-CD20 mAb Rituximab has revolutionized lymphoma therapy, in spite of a number of unresponsive or relapsing patients. Immunotoxins, consisting of toxins coupled to antibodies, are being investigated for their potential ability to augment Rituximab efficacy. Here, we compare the anti-tumor effect of high- and low-molecular-weight Rituximab/saporin-S6 immunotoxins, named HMW-IT and LMW-IT, respectively. Saporin-S6 is a potent and stable plant enzyme belonging to ribosome-inactivating proteins that causes protein synthesis arrest and consequent cell death. Saporin-S6 was conjugated to Rituximab through an artificial disulfide bond. The inhibitory activity of HMW-IT and LMW-IT was evaluated on cell-free protein synthesis and in two CD20+ lymphoma cell lines, Raji and D430B. Two different conjugates were separated on the basis of their molecular weight and further characterized. Both HMW-IT (dimeric) and LMW-IT (monomeric) maintained a high level of enzymatic activity in a cell-free system. HMW-IT, thanks to a higher toxin payload and more efficient antigen capping, showed stronger in vitro anti-tumor efficacy than LMW-IT against lymphoma cells. Dimeric HMW-IT can be used for lymphoma therapy at least for ex vivo treatments. The possibility of using HMW-IT augments the yield in immunotoxin preparation and allows the targeting of antigens with low internalization rates. PMID:27338475

  1. High in Vitro Anti-Tumor Efficacy of Dimeric Rituximab/Saporin-S6 Immunotoxin.

    PubMed

    Bortolotti, Massimo; Bolognesi, Andrea; Battelli, Maria Giulia; Polito, Letizia

    2016-01-01

    The anti-CD20 mAb Rituximab has revolutionized lymphoma therapy, in spite of a number of unresponsive or relapsing patients. Immunotoxins, consisting of toxins coupled to antibodies, are being investigated for their potential ability to augment Rituximab efficacy. Here, we compare the anti-tumor effect of high- and low-molecular-weight Rituximab/saporin-S6 immunotoxins, named HMW-IT and LMW-IT, respectively. Saporin-S6 is a potent and stable plant enzyme belonging to ribosome-inactivating proteins that causes protein synthesis arrest and consequent cell death. Saporin-S6 was conjugated to Rituximab through an artificial disulfide bond. The inhibitory activity of HMW-IT and LMW-IT was evaluated on cell-free protein synthesis and in two CD20⁺ lymphoma cell lines, Raji and D430B. Two different conjugates were separated on the basis of their molecular weight and further characterized. Both HMW-IT (dimeric) and LMW-IT (monomeric) maintained a high level of enzymatic activity in a cell-free system. HMW-IT, thanks to a higher toxin payload and more efficient antigen capping, showed stronger in vitro anti-tumor efficacy than LMW-IT against lymphoma cells. Dimeric HMW-IT can be used for lymphoma therapy at least for ex vivo treatments. The possibility of using HMW-IT augments the yield in immunotoxin preparation and allows the targeting of antigens with low internalization rates. PMID:27338475

  2. Target-directed development and preclinical characterization of the proposed biosimilar rituximab GP2013

    PubMed Central

    Kronthaler, Ulrich; Koppenburg, Vera; Fink, Martin; Meyer, Ines; Papandrikopoulou, Anastassia; Hofmann, Matthias; Stangler, Thomas; Visser, Jan

    2014-01-01

    Biosimilar development involves a target-directed iterative process to ensure a similar product to the originator. Here we report the preclinical development of the proposed biosimilar rituximab (GP2013). Post-translational modifications and bioactivities of GP2013 versus originator rituximab were engineered and monitored to ensure similar pharmacological profiles. Antibody-dependent cellular cytotoxicity (ADCC) was used to illustrate how different glycosylation patterns and structure–function relationships were controlled during process development. Pharmacological comparability between GP2013 and originator rituximab were confirmed in preclinical studies using clinical scale drug product. Similar in vitro ADCC potency was demonstrated when compared in a dose–response manner against two lymphoma cell lines using freshly purified human natural killer (NK) cells. In vivo efficacy was demonstrated in two well characterized mouse xenograft models, testing at sensitive sub-therapeutic dose levels. Pharmacokinetics and pharmacodynamics (CD20 cell depletion) were likewise comparable in cynomolgus monkeys. This preclinical comparability exercise confirms that GP2013 and originator rituximab are pharmacologically similar. PMID:24024472

  3. Treatment of recurrent focal segmental glomerulosclerosis in pediatric kidney transplant recipients: effect of rituximab.

    PubMed

    Sethna, Christine; Benchimol, Corinne; Hotchkiss, Hilary; Frank, Rachel; Infante, Lulette; Vento, Suzanne; Trachtman, Howard

    2011-01-01

    Recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation is a complication that often leads to graft loss. There is no consensus on the optimal treatment of recurrent FSGS. Rituximab, a monoclonal antibody to CD20, may be a useful treatment of this complication. Methods. We report four pediatric cases of recurrent FSGS treated with rituximab and plasmapheresis. Results. Four children (2M/2F), age 15.3 ± 2.6, with recurrent FSGS posttransplant were identified. Four doses of rituximab were administered 171 ± 180 days posttransplant and 114 ± 169 days after the start of plasmapheresis. Three children responded with complete remission, one of whom relapsed after four months. One child had a partial response with a decrease in proteinuria that was not sustained. No adverse side effects were reported during treatment or followup (mean 22.5 months). Conclusions. Rituximab is a safe and well-tolerated ancillary treatment for recurrent FSGS in pediatric patients in conjunction with plasmapheresis. PMID:21577271

  4. Treatment of Recurrent Focal Segmental Glomerulosclerosis in Pediatric Kidney Transplant Recipients: Effect of Rituximab

    PubMed Central

    Sethna, Christine; Benchimol, Corinne; Hotchkiss, Hilary; Frank, Rachel; Infante, Lulette; Vento, Suzanne; Trachtman, Howard

    2011-01-01

    Recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation is a complication that often leads to graft loss. There is no consensus on the optimal treatment of recurrent FSGS. Rituximab, a monoclonal antibody to CD20, may be a useful treatment of this complication. Methods. We report four pediatric cases of recurrent FSGS treated with rituximab and plasmapheresis. Results. Four children (2M/2F), age 15.3 ± 2.6, with recurrent FSGS posttransplant were identified. Four doses of rituximab were administered 171 ± 180 days posttransplant and 114 ± 169 days after the start of plasmapheresis. Three children responded with complete remission, one of whom relapsed after four months. One child had a partial response with a decrease in proteinuria that was not sustained. No adverse side effects were reported during treatment or followup (mean 22.5 months). Conclusions. Rituximab is a safe and well-tolerated ancillary treatment for recurrent FSGS in pediatric patients in conjunction with plasmapheresis. PMID:21577271

  5. Combination Radioimmunotherapy Approaches and Quantification of Immuno-PET.

    PubMed

    Kim, Jin Su

    2016-06-01

    Monoclonal antibodies (mAbs), which play a prominent role in cancer therapy, can interact with specific antigens on cancer cells, thereby enhancing the patient's immune response via various mechanisms, or mAbs can act against cell growth factors and, thereby, arrest the proliferation of tumor cells. Radionuclide-labeled mAbs, which are used in radioimmunotherapy (RIT), are effective for cancer treatment because tumor associated-mAbs linked to cytotoxic radionuclides can selectively bind to tumor antigens and release targeted cytotoxic radiation. Immunological positron emission tomography (immuno-PET), which is the combination of PET with mAb, is an attractive option for improving tumor detection and mAb quantification. However, RIT remains a challenge because of the limited delivery of mAb into tumors. The transport and uptake of mAb into tumors is slow and heterogeneous. The tumor microenvironment contributed to the limited delivery of the mAb. During the delivery process of mAb to tumor, mechanical drug resistance such as collagen distribution or physiological drug resistance such as high intestinal pressure or absence of lymphatic vessel would be the limited factor of mAb delivery to the tumor at a potentially lethal mAb concentration. When α-emitter-labeled mAbs were used, deeper penetration of α-emitter-labeled mAb inside tumors was more important because of the short range of the α emitter. Therefore, combination therapy strategies aimed at improving mAb tumor penetration and accumulation would be beneficial for maximizing their therapeutic efficacy against solid tumors. PMID:27275358

  6. Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

    PubMed Central

    2011-01-01

    Introduction Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean

  7. A phase II trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701

    PubMed Central

    Grant, Barbara W.; Jung, Sin-Ho; Johnson, Jeffrey L.; Kostakoglu, Lale; His, Eric; Byrd, John C.; Jones, Jeffrey; Leonard, John P.; Martin, S. Eric; Cheson, Bruce D.

    2013-01-01

    Rituximab combined with chemotherapy has improved the survival of previously untreated patients with follicular lymphoma (FL). Nevertheless, many patients neither want nor can tolerate chemotherapy, leading to interest in biological approaches. Epratuzumab is a humanized anti-CD22 monoclonal antibody with efficacy in relapsed FL. Since both rituximab and epratuzumab have single agent activity in FL, we evaluated the antibody combination as initial treatment of patients with FL. Patients and Methods Fifty-nine untreated patients with FL received epratuzumab 360 mg/m2 with rituximab 375 mg/m2 weekly for four induction doses. This combination was continued as extended induction in weeks 12, 20, 28, and 36. Response assessed by CT was correlated with clinical risk factors, FDG-PET findings at week 3, Fcg polymorphisms, immunohistochemical markers, and statin use. Results Therapy was well-tolerated with toxicities similar to expected with rituximab monotherapy. Fifty-two (88.2%) evaluable patients responded, including 25 complete responses (CR)(42.4%), and 27 partial responses (45.8%). At 3 years follow-up, 60% of patients remain in remission. Follicular Lymphoma International Prognostic Index (FLIPI) risk strongly predicted progression-free survival (p=0.022). Conclusions The high response rate and prolonged time to progression observed with this antibody combination are comparable to those observed after standard chemo-immunotherapies and further support the development of biologic, non-chemotherapeutic approaches for these patients. PMID:23922187

  8. Association between -174 interleukin-6 gene polymorphism and biological response to rituximab in several systemic autoimmune diseases.

    PubMed

    Robledo, Gema; Dávila-Fajardo, Cristina Lucía; Márquez, Ana; Ortego-Centeno, Norberto; Callejas Rubio, José Luis; de Ramón Garrido, Enrique; Sánchez-Román, Julio; García-Hernández, Francisco J; Ríos-Fernández, Raquel; González-Escribano, Maria Francisca; Camps García, Maria Teresa; Castillo Palma, Maria Jesús; Ayala, Maria Del Mar; Martín, Javier

    2012-09-01

    Rituximab has become a pivotal treatment for systemic autoimmune diseases. The aim of this study was to determine whether the genetic variant -174 IL-6 contributes to differences in the response to rituximab in patients with systemic autoimmune diseases, including systemic lupus erythematosus (SLE), inflammatory myopathies, anti-neutrophil cytoplasmic antibody-mediated vasculitis, systemic sclerosis, Sjöegren's syndrome, rheumatoid arthritis, and autoimmune hemolytic anemia. DNA samples from 144 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for -174 IL-6 (rs1800795) gene polymorphism using the TaqMan(®) allelic discrimination technology. Six months after the first infusion with rituximab, we evaluated the response to the drug: 60.4% of the patients showed a complete response, partial 27.8%, and 11.8% did not respond to the treatment. The CC genotype frequency was significantly increased in nonresponders with respect to responders (23.5% vs. 7.1%, respectively; p=0.049; odds ratio (OR)=4.03, 95% confidence intervals (CI) 0.78-16.97). According to the genotype distribution, rituximab was effective in 69.2% of the CC carriers, 91.9% of the CG carriers, and 88.4% of the GG carriers. A similar trend was observed when SLE patients were analyzed separately (27.3% carried CC homozygosis in nonresponders and 6.9% in responders; p=0.066; OR=5.10, 95% CI 0.65-31.73). Rituximab was effective in 62.5% of the CC carriers, 88.9% of the GC carriers, and 90% of the GG carriers. These results suggest that -174 IL-6 (rs1800795) gene polymorphism plays a role in the response to rituximab in systemic autoimmune diseases. Validation of these findings in independent cohorts is warranted. PMID:22734797

  9. Future therapies for pemphigus vulgaris: Rituximab and beyond.

    PubMed

    Huang, Amy; Madan, Raman K; Levitt, Jacob

    2016-04-01

    The conventional treatment for patients with pemphigus vulgaris (PV) centers on global immunosuppression, such as the use of steroids and other immunosuppressive drugs, to decrease titers of antidesmoglein autoantibodies responsible for the acantholytic blisters. Global immunosuppressants, however, cause serious side effects. The emergence of anti-CD20 biologic medications, such as rituximab, as an adjunct to conventional therapy has shifted the focus to targeted destruction of autoimmune B cells. Next-generation biologic medications with improved modes of delivery, pharmacology, and side effect profiles are constantly being developed, adding to the diversity of options for PV treatment. We review promising monoclonal antibodies, including veltuzumab, obinutuzumab (GA-101), ofatumumab, ocaratuzumab (AME-133v), PRO131921, and belimumab. PMID:26792592

  10. Rituximab-induced interstitial lung disease: five case reports.

    PubMed

    Naqibullah, Matiuallah; Shaker, Saher B; Bach, Karen S; Bendstrup, Elisabeth

    2015-01-01

    Rituximab (RTX), a mouse/human chimeric anti-CD20 IgG1 monoclonal antibody has been effectively used as a single agent or in combination with chemotherapy regimen to treat lymphoma since 1997. In addition, it has been used to treat idiopathic thrombocytopenic purpura, systemic lupus erythematous, rheumatoid arthritis, and autoimmune hemolytic anemia. Recently, RTX has also been suggested for the treatment of certain connective tissue disease-related interstitial lung diseases (ILD) and hypersensitivity pneumonitis. Rare but serious pulmonary adverse reactions are reported. To raise awareness about this serious side effect of RTX treatment, as the indication for its use increases with time, we report five cases of probable RTX-ILD and discuss the current literature on this potentially lethal association. PMID:26557260

  11. A Case of Fulminant Hepatitis due to Echovirus 9 in a Patient on Maintenance Rituximab Therapy for Follicular Lymphoma

    PubMed Central

    Thomson, S. J.; Legg, Joanne; Narat, Santosh

    2015-01-01

    Rituximab is a CD20 monoclonal antibody commonly used in the treatment of haematological malignancies. It causes lymphopenia with subsequent compromised humoral immunity resulting in an increased risk of infection. A number of infections and viral reactivations have been described as complicating Rituximab therapy. We report an apparently unique case of echovirus 9 (an enterovirus) infection causing an acute hepatitis and significant morbidity in an adult patient on maintenance treatment of Rituximab for follicular lymphoma. We also describe potential missed opportunities to employ more robust screening for viral infections which may have prevented delays in the appropriate treatment and thus may have altered the patient's clinical course. We also make suggestions for lowering the threshold of viral testing in similar patients in the future. PMID:26106492

  12. Idiopathic Nonviral Cryoglobulinemia Treated Successfully With Rituximab.

    PubMed

    Kamel, Mahmoud; Thajudeen, Bijin; Bracamonte, Erika; Madhrira, Machaiah

    2016-01-01

    Cryoglobulinemia is a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. The therapeutic management of idiopathic cryoglobulinemic vasculitis has yet to be defined because no study has evaluated the best strategies. However, treatment of severe vasculitis is traditionally based on a combination of corticosteroids and immunosuppressants or plasmapheresis, and more recently rituximab. We report a case of 77-year-old female patient diagnosed with idiopathic cryoglobulinemia, treated successfully with 6 months prednisone tapering and 2 doses of rituximab (1 g each dose). After receiving the above-mentioned treatment, her creatinine went back to normal with resolution of proteinuria and hematuria, normalization of serum complements, and significant improvement in her clinical picture. We conclude that rituximab could be an effective treatment for idiopathic cryoglobulnemia. PMID:24914502

  13. Development of Novel Anti-Cd20 Monoclonal Antibodies and Modulation in Cd20 Levels on Cell Surface: Looking to Improve Immunotherapy Response

    PubMed Central

    Singh, Vijay; Gupta, Damodar; Almasan, Alexandru

    2016-01-01

    Rituximab has been revolutionized and validated CD20 targeting monoclonal antibody. Although, it is widely used for lymphoma therapy and many patients have been benefited. However significant numbers of patients are refractory or developed resistance to current therapies due to low level of CD20 expression and/or availability on cells surface. Thus development of novel anti-CD20 mAbs with great cell killing ability and enhance CD20 levels on cell surface can potentially exploit lymphoma therapy. In this scenario, we are summarizing the recently developed mAbs against CD20 and compounds that have ability to induce CD20 expression at significant level. We also are providing information regarding combination strategy for use of radiation and anti-CD20 mAbs in vitro. However, it will need to be determined by rigorous at pre-clinical and clinic testing. We hope this review will be beneficial for current research in the area of immunotherapy or radio-immunotherapy. PMID:27413424

  14. Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor.

    PubMed

    Perosa, Federico; Favoino, Elvira; Caragnano, Maria Antonietta; Dammacco, Franco

    2006-02-01

    Heterogeneity of the effector functions displayed by rituximab and other anti-CD20 monoclonal antibodies (mAbs) apparently recognizing the same CD20 epitope suggests that additional mechanisms, probably related to mAb fine specificity, are responsible for B-cell depletion. To improve our understanding of rituximab's function, its fine specificity was investigated by means of phage display peptide library (PDPL)-expressing 7-mer cyclic (c7c) or 7-/12-mer linear peptides. Rituximab-specific c7c PDPL-derived clone insert sequences expressed the motif A(S)NPS overlapping the human CD20 170ANPS173. P172 was the most critical for rituximab binding, since its replacement with S172 (of mouse CD20) abolished the reactivity. The WPXWLE motif expressed by the linear PDPL-derived clone insert sequences could only be aligned to the reverse-oriented 161WPXWLE156 of acid sphingomyelinase-like phosphodiesterase 3b precursor (ASMLPD), though linear peptides bearing WPXWLE competed with cyclic ones for rituximab-paratope binding. Anti-CD20 mAb 1F5 only displayed a reactivity profile similar to that of rituximab, which also reacted with ASMLPD-derived peptides. Peptides induced antibodies with specificity and effector functions similar to those of rituximab. Our results show a unique fine specificity of rituximab, define the molecular basis for the lack of rituximab reactivity with mouse CD20 (mCD20), and the potential of targeting CD20 in an active immunotherapy setting. A possible rituximab interaction with ASMLPD is suggested. PMID:16223774

  15. Characterization of Self-Assembled Monolayers of Peptide Mimotopes of CD20 Antigen and Their Binding with Rituximab.

    PubMed

    Leo, Norman; Shang, Yuqin; Yu, Jing-jiang; Zeng, Xiangqun

    2015-12-29

    CD20, expressed in greater than 90% of B-lymphocytic lymphomas, is a target for antibody therapy. Rituximab is a chimeric therapeutic monoclonal antibody (mAb) against the protein CD20, allowing it to destroy B cells and to treat lymphoma, leukemia, transplant rejection, and autoimmune disorder. In this work, the binding of rituximab to self-assembled monolayers (SAMs) of peptide mimotopes of CD20 antigen was systematically characterized. Four peptide mimotopes of CD 20 antigen were selected from the literature and redesigned to allow their SAM immobilizations on gold electrodes through a peptide linker with cysteine. The bindings of these peptides with rituximab and control mAbs (trastuzumab and bevacizumab) were characterized by quartz crystal microbalance (QCM). Among the four peptide mimotopes initially selected, the peptide designated as CN-14 (CGSGSGSWPRWLEN) was the most selective and sensitive for rituximab binding. The CN-14 SAM was further characterized by ellipsometry and atomic force microscopy. The thickness of the CN-14 SAM film was approximately 32 Å, and the CN-14 SAM is suggested to be stabilized by a salt bridge of Arg-10 and Glu-13 between CN-14 peptides. The CN-14 salt bridge was evaluated by a series of modifications to the CN-14 peptide sequence and characterized by QCM. The CN-14 amide variant produced a better affinity to rituximab than CN-14 without a significant impact on selectivity. As the pKa of the Glu residue of CN-14 increased, the affinity of the SAM to rituximab increased, whereas the selectivity decreased. This was attributed to the weakening of the salt bridge between the CN-14 Arg-10 and Glu-13 at higher pKa values for Glu-13. Our study shows that peptide mimotopes have potential benefits in sensor applications, as the peptide-peptide interactions in the SAMs can be manipulated by the addition of functional groups to the peptide to influence the binding of target proteins. PMID:26609837

  16. Herpetic tracheitis in association with rituximab therapy.

    PubMed

    Thong, Lorraine; Plant, Barry J; McCarthy, Julie; Murphy, Desmond M

    2016-07-01

    A 58-year old lady under active follow-up with the respiratory services at our institution for bronchiectasis secondary to hypogammaglobulinaemia presented with hoarseness and haemoptysis. She was also receiving rituximab maintenance therapy for follicular lymphoma. Bronchoscopy demonstrated vesicular lesions on her vocal cords and trachea, confirmed as herpes simplex virus (HSV) on cytological analysis of brushings. She responded well to intravenous valacyclovir. Rituximab is increasingly utilised in the treatment of haematological and auto-immune disorders. This case highlights the potential of this drug to potentiate susceptibility to infection in an already immunocompromised individual. PMID:27512561

  17. Protein-losing enteropathy associated with refractory systemic lupus erythematosus with a good response to rituximab.

    PubMed

    Sansinanea, Pierina; Carrica, Sebastián Augusto; Marcos, Josefina; García, Mercedes Argentina

    2016-01-01

    A case is presented of a protein-losing enteropathy (PLE) as the initial manifestation of systemic lupus erythematosus (SLE) in a 17 year-old female patient, who presented with ascites, edema and hypoalbuminemia. The diagnosis of SLE was based on the presence of: malar rash, oral ulcers, thrombocytopenia, antinuclear antibodies, IgM anticardiolipin antibody, and lupus anticoagulant. Renal and liver diseases were ruled out. The PLE diagnosis was confirmed with fecal alpha 1-antitrypsin clearance. The PLE was refractory to different lines of immunosuppressive agents like glucocorticoids, cyclophosphamide, azathioprine, and cyclosporine, showing a satisfactory and sustained response with rituximab, allowing steroid sparing and long term remission. PMID:25818375

  18. Placebo-controlled trial of rituximab in IgM anti-myelin–associated glycoprotein neuropathy

    PubMed Central

    Viala, Karine; Nicolas, Guillaume; Créange, Alain; Vallat, Jean-Michel; Pouget, Jean; Clavelou, Pierre; Vial, Christophe; Steck, Andreas; Musset, Lucile; Marin, Benoit

    2013-01-01

    Objective: To determine whether rituximab 375 mg/m2 was efficacious in patients with immunoglobulin M (IgM) anti-myelin–associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy). Methods: Fifty-four patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) ≥4 and visual analog pain scale >4 or ataxia score ≥2. The primary outcome was mean change in ISS at 12 months. Results: Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m2 rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 ± 2.7 in the rituximab group, and 1.0 ± 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p = 0.027), the self-evaluation scale (p = 0.016), and 2 subscores of the Short Form–36 questionnaire. Conclusions: Although primary outcome measures provide no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis. Level of evidence: This study provides Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy. PMID:23667063

  19. Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally

    PubMed Central

    Bergman, Joakim; Dring, Ann; Vågberg, Mattias; Birgander, Richard; Lindqvist, Thomas; Gilthorpe, Jonathan; Bergenheim, Tommy

    2015-01-01

    Objective: We are conducting an open-label phase 1b study on the efficacy of intrathecal (IT) administration of rituximab, provided via an Ommaya reservoir, for the treatment of progressive multiple sclerosis (PMS). The objective of this initial study was to monitor B lymphocytes in peripheral blood (PB) and CSF from the first 10 patients 1 year posttreatment. Methods: Dose titration was performed with daily escalation from 1 mg to 25 mg IT rituximab (n = 3). Lymphocyte subpopulations were monitored daily during dose escalation in PB by flow cytometry and subsequently every 3 months for 1 year, after a total dose of 3 × 25 mg. PB B-lymphocyte subpopulations for the remaining patients (n = 7) were monitored at regular intervals. CSF lymphocyte subpopulations for all patients were monitored by flow cytometry every 2–3 months. Results: The PB B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3–6 month period. Conclusions: Monoclonal antibodies seem to rapidly redistribute to the peripheral compartment following IT injection. Ultra-low doses of rituximab given IT are sufficient to cause complete depletion of peripheral B lymphocytes, indicating that low-dose IT treatment has the potential to be effective in both the CNS and systemic compartments. Classification of evidence: This study provides Class IV evidence that for patients with PMS, rituximab provided via an Ommaya reservoir depletes peripheral blood B lymphocytes. PMID:25745637

  20. The Role of PAM4 in the Management of Pancreatic Cancer: Diagnosis, Radioimmunodetection, and Radioimmunotherapy

    PubMed Central

    Han, Suxia; Jin, Guihua; Wang, Lijuan; Li, Meng; He, Chenchen; Guo, Xijing; Zhu, Qing

    2014-01-01

    PAM4, a new monoclonal antibody (MAb) known as clivatuzumab, is highly reactive with pancreatic cancer and precursor lesions. It is absent from the normal tissues and has limited reactivity with nonpancreatic cancer. The detailed characteristic of the PAM4 epitope is unknown but recent studies have shown that it is dependent on MUC1 glycosylation status. The limited PAM4 expression pattern makes it an attractive candidate for management of pancreatic adenocarcinoma. In addition, PAM4 is a serum biomarker for diagnosis of pancreatic cancer. Several different radiolabeled immunodiagnostic and immunotherapeutic agents of PAM4 have been developed and some are being evaluated in preclinical and/or clinical studies. The review will focus on PAM4 and its potential utility for the diagnosis, radioimmunodetection, and radioimmunotherapy of pancreatic cancer. PMID:24818166

  1. Radioisotopes for radioimmunodetection (RAID) and radioimmunotherapy (RAIT)---current and new perspectives

    SciTech Connect

    Knapp, F.F. Jr.

    1991-01-01

    In this paper the availability and properties of radioisotopes for both radioimmunodiagnosis (RAID) and radioimmunotherapy (RAIT) are discussed. Examples are provided for radioisotopes available via direct production in nuclear reactors and accelerators or as daughters obtained from radionuclide generator systems whose parents are either reactor or accelerator produced. Important factors which must be considered for the use of a particular radioisotope include availability, the physical half-life and decay properties, and chemical versatility for protein attachment. Although both direct'' and indirect'' methods are available for attachment of radioisotopes to antibodies, this broad field of research is not reviewed in detail. Practical issues related to the availability and use of a variety of radionuclides are described. 47 refs., 5 tabs.

  2. Emerging Trends for Radioimmunotherapy in Solid Tumors

    PubMed Central

    Gupta, Suprit; Kaur, Sukhwinder; Ponnusamy, Moorthy P.

    2013-01-01

    Abstract Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and undesirable pharmacokinetics, however, have precluded the administration of radioimmunoconjugates at therapeutically relevant doses thereby limiting the clinical utility of RIT. In solid tumors, efficacy of RIT is further compromised by heterogeneities in blood flow, tumor stroma, expression of target antigens and radioresistance. As a result significant efforts have been invested toward developing strategies to overcome these impediments. Further, there is an emerging interest in exploiting short-range, high energy α-particle emitting radionuclides for the eradication of minimal residual and micrometastatic disease. As a result several modalities for localized therapy and models of minimal disease have been developed for preclinical evaluation. This review provides a brief update on the recent efforts toward improving the efficacy of RIT for solid tumors, and development of RIT strategies for minimal disease associated with solid tumors. Further, some of promising approaches to improve tumor targeting, which showed promise in the past, but have now been ignored are also discussed. PMID:23844555

  3. Fractionated Radioimmunotherapy With 90Y-Clivatuzumab Tetraxetan and Low-Dose Gemcitabine Is Active in Advanced Pancreatic Cancer

    PubMed Central

    Ocean, Allyson J.; Pennington, Kenneth L.; Guarino, Michael J.; Sheikh, Arif; Bekaii-Saab, Tanios; Serafini, Aldo N.; Lee, Daniel; Sung, Max W.; Gulec, Seza A.; Goldsmith, Stanley J.; Manzone, Timothy; Holt, Michael; O’Neil, Bert H.; Hall, Nathan; Montero, Alberto J.; Kauh, John; Gold, David V.; Horne, Heather; Wegener, William A.; Goldenberg, David M.

    2014-01-01

    BACKGROUND It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2–4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. RESULTS Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at

  4. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic

    PubMed Central

    Richter, Maximilian; Yumul, Roma; Saydaminova, Kamola; Wang, Hongjie; Gough, Michael; Baldessari, Audrey; Cattaneo, Roberto; Lee, Frank; Wang, Chung-Huei Katherine; Jang, Haishan; Astier, Anne; Gopal, Ajay; Carter, Darrick; Lieber, André

    2016-01-01

    Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the

  5. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic.

    PubMed

    Richter, Maximilian; Yumul, Roma; Saydaminova, Kamola; Wang, Hongjie; Gough, Michael; Baldessari, Audrey; Cattaneo, Roberto; Lee, Frank; Wang, Chung-Huei Katherine; Jang, Haishan; Astier, Anne; Gopal, Ajay; Carter, Darrick; Lieber, André

    2016-01-01

    Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the

  6. Prediction of tumor response to experimental radioimmunotherapy with {sup 90}Y in nude mice

    SciTech Connect

    Dillehay, L.E.; Mayer, R.; Zhang, Y.G.

    1995-09-30

    The purpose of this investigation was to identify those factors that predict variability in tumor response to {sup 90}Y-radioimmunotherapy based on measurement of incorporated activity and physical dimensions of individual tumors and to apply the concept of effective dose to radioimmunotherapy. Human colon carcinoma xenografts growing in nude mice were treated with anti-CEA antibodies labeled with {sup 90}Y directly or through a bispecific antibody/labeled hapten system. Tumor response was measured as the delay in growth to eight times the treatment volume. Noninvasive activity (based on bremsstrahlung radiation) and dimension measurements were made in these animals at several times after label injection. The following parameters were compared for their ability to predict individual tumor response: (a) injected activity, (b) injected activity times a factor based on average uptake as a function of volume, (c) in vivo activity per volume measured in each animal at a single time, (d) the integral over time of in vivo activity per volume in each animal, and (e) the minimum dose for each animal in a uniformly active ellipsoid whose total activity and dimensions varied over time the same as the tumor. After correcting for differences in injected activity, two parameters account for much of the variability in tumor response. One of these is the general trend of larger tumors to take up less activity per volume. Additional variability can be accounted for by the in vivo activity per volume measurements. The minimum dose as introduced here is likely to be useful in estimating the biologically effective dose delivered by each treatment. 27 refs., 5 figs., 1 tab.

  7. Assessment of physicochemical properties of rituximab related to its immunomodulatory activity.

    PubMed

    Miranda-Hernández, Mariana P; López-Morales, Carlos A; Ramírez-Ibáñez, Nancy D; Piña-Lara, Nelly; Pérez, Nestor O; Molina-Pérez, Aarón; Revilla-Beltri, Jorge; Flores-Ortiz, Luis F; Medina-Rivero, Emilio

    2015-01-01

    Rituximab is a chimeric monoclonal antibody employed for the treatment of CD20-positive B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. It binds specifically to the CD20 antigen expressed on pre-B and consequently on mature B-lymphocytes of both normal and malignant cells, inhibiting their proliferation through apoptosis, CDC, and ADCC mechanisms. The immunomodulatory activity of rituximab is closely related to critical quality attributes that characterize its chemical composition and spatial configuration, which determine the recognition of CD20 and the binding to receptors or factors involved in its effector functions, while regulating the potential immunogenic response. Herein, we present a physicochemical and biological characterization followed by a pharmacodynamics and immunogenicity study to demonstrate comparability between two products containing rituximab. The physicochemical and biological characterization revealed that both products fit within the same response intervals exhibiting the same degree of variability. With regard to clinical response, both products depleted CD20+ B-cells until posttreatment recovery and no meaningful differences were found in their pharmacodynamic profiles. The evaluation of anti-chimeric antibodies did not show differential immunogenicity among products. Overall, these data confirm that similarity of critical quality attributes results in a comparable immunomodulatory activity. PMID:25973441

  8. Assessment of Physicochemical Properties of Rituximab Related to Its Immunomodulatory Activity

    PubMed Central

    Miranda-Hernández, Mariana P.; López-Morales, Carlos A.; Ramírez-Ibáñez, Nancy D.; Piña-Lara, Nelly; Pérez, Nestor O.; Molina-Pérez, Aarón; Revilla-Beltri, Jorge; Flores-Ortiz, Luis F.

    2015-01-01

    Rituximab is a chimeric monoclonal antibody employed for the treatment of CD20-positive B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. It binds specifically to the CD20 antigen expressed on pre-B and consequently on mature B-lymphocytes of both normal and malignant cells, inhibiting their proliferation through apoptosis, CDC, and ADCC mechanisms. The immunomodulatory activity of rituximab is closely related to critical quality attributes that characterize its chemical composition and spatial configuration, which determine the recognition of CD20 and the binding to receptors or factors involved in its effector functions, while regulating the potential immunogenic response. Herein, we present a physicochemical and biological characterization followed by a pharmacodynamics and immunogenicity study to demonstrate comparability between two products containing rituximab. The physicochemical and biological characterization revealed that both products fit within the same response intervals exhibiting the same degree of variability. With regard to clinical response, both products depleted CD20+ B-cells until posttreatment recovery and no meaningful differences were found in their pharmacodynamic profiles. The evaluation of anti-chimeric antibodies did not show differential immunogenicity among products. Overall, these data confirm that similarity of critical quality attributes results in a comparable immunomodulatory activity. PMID:25973441

  9. B-cell targeted therapy with rituximab for thyroid eye disease: closer to the clinic.

    PubMed

    Shen, Sunny; Chan, Anita; Sfikakis, Petros P; Hsiu Ling, Andrea Low; Detorakis, Efstathios T; Boboridis, Kostas G; Mavrikakis, Ioannis

    2013-01-01

    The management of thyroid eye disease (TED) remains a therapeutic challenge. The current established therapies are unsatisfactory in one-third of the patients and have many limitations. Rituximab (RTX) is a CD20+ B-cell-depleting monoclonal antibody approved for the treatment of non-Hodgkin lymphomas, chronic lymphocytic leukemia, and rheumatoid arthritis. The early experience with RTX suggests that it is a promising alternative therapy for TED. Rituximab may compare favorably to the conventional glucocorticoid therapy and causes less collateral damage than retrobulbar orbital radiation and decompression surgery. In addition, the preliminary studies on RTX's proposed mechanism of action have revealed new insights into the pathogenic role of B-cells in TED. We summarize the current literature on the clinical application of RTX in TED and discuss its putative mechanisms of action. PMID:23253433

  10. Rituximab-induced neutropenia in a patient with inflammatory myopathy and systemic sclerosis overlap disease

    PubMed Central

    Roberts, Mark; Oddis, Chester; Herrick, Arianne; Chinoy, Hector

    2016-01-01

    Rituximab (RTX) is a monoclonal chimeric antibody directed against the CD20 antigen of B lymphocytes. Late onset neutropenia (LON) is a recognised complication of rituximab usually occurring 4 weeks after the last dose and is reported in both haematological and rheumatological conditions. However, it has never been described in a patient with myositis and systemic sclerosis overlap disease. We describe a case of LON in a 54-year-old man who was diagnosed with myositis and then systemic sclerosis overlap disease. It resolved within 7 days, and the patient did not suffer neutropenic sepsis or any other complications. We propose similar mechanisms for LON as described in other conditions and routine blood monitoring in such patients. PMID:27407275

  11. Treatment of leukemia with radiolabeled monoclonal antibodies.

    PubMed

    Sgouros, G; Scheinberg, D A

    1993-01-01

    In contrast to radioimmunotherapy of solid disease, wherein the primary obstacle to success is access of radiolabeled antibody to antigen-positive cells, in the treatment of leukemia delivering a lethal absorbed dose to the isolated cell appears to be the primary obstacle. The isolated cell is defined as one that is exposed only to self-irradiation (from internalized or surface-bound radiolabeled antibody) and to irradiation from free antibody in the blood. It is isolated in the sense that the particulate (beta, electron, alpha) emissions from its nearest neighboring antigen-positive cell do not contribute to its absorbed dose. Disease in the bone marrow and other tissues, since it is confined to a smaller volume, is more easily eradicated because the absorbed dose to a given cell nucleus is enhanced by emissions from adjacent cells (a smaller fraction of the emission energy is 'wasted'). The optimization simulations presented above for the M195 antibody suggest that the optimum dose of antibody that should be administered is that required to yield a concentration within the distribution volume of the antibody that is approximately equal to the concentration of antigen sites as determined by the tumor burden. Although not specifically considered in the modeling example presented above, antibody internalization and catabolism may be expected to play an important role in radioimmunotherapy treatment planning of leukemia. Depending upon the kinetics of internalization and catabolism, the absorbed dose to the red marrow and to antigen-positive cells may be reduced considerably, since catabolism, assuming that it is followed by rapid extrusion of the radioactive label, would decrease the cells' exposure time considerably. The recently demonstrated effectiveness of radioimmunotherapy in certain cases of B-cell lymphoma and in reducing tumor burden in acute myelogenous leukemia suggests that radioimmunotherapy is beginning to fulfill the promise held when it was initially

  12. Successful Treatment of Life-Threatening Interstitial Lung Disease Secondary to Antisynthetase Syndrome Using Rituximab: A Case Report and Review of the Literature.

    PubMed

    Dasa, Osama; Ruzieh, Mohammed; Oraibi, Omar

    2016-01-01

    We are presenting a case of antisynthetase syndrome (ASS) that manifested with severe interstitial pneumonitis in the presence of anti-Jo-1 and Ro (SSA) antibodies. Our patient developed respiratory failure with high oxygen requirements despite treatment by high-dose steroids. The patient was then treated with rituximab. This treatment led to significant improvement in the patient condition, with resolution of the ground glass opacities on high-resolution computerized tomography and near normalization of pulmonary function tests. In this communication, we performed a literature review and summarized previous reports pertinent to using of rituximab to treat interstitial lung disease (ILD) secondary to ASS by searching the PubMed database from 1980 to 2014. We were able to find 14 reports that included total of 45 patients with ILD secondary to ASS. A significant improvement in ILD was reported in the majority of reported patients who received rituximab, while there was only 1 mortality-related to Pneumocystis jirovecii pneumonia. Rituximab treatment was tolerated well in the majority of cases. It is our conclusion that rituximab can be considered a therapeutic option in ILD secondary to ASS based on our experience with this case and the currently available evidence in the literature. Nevertheless, there is a need for additional controlled studies to assess the efficacy and safety of rituximab in ILD secondary to ASS compared with other immunosuppressive regimens. PMID:25830868

  13. Rituximab in combination with platinum-containing chemotherapy in patients with relapsed or primary refractory diffuse large B-cell lymphoma.

    PubMed

    Bieker, Ralf; Kessler, Torsten; Berdel, Wolfgang E; Mesters, Rolf M

    2003-01-01

    The aim of the study was to evaluate the efficacy of a regimen consisting of rituximab and a platinum-containing chemotherapy with either Ifosfamide, Carboplatin and Etoposide (ICE) or Cisplatin, high-dose Ara-C and Dexamethasone (DHAP) in patients with relapsed or primary refractory diffuse large B-cell lymphoma. Ten patients with relapsed or primary refractory diffuse large B-cell lymphoma were treated from June 2000 until May 2001 with a platinum-containing chemotherapy regimen according to the ICE- or DHAP-protocol in combination with rituximab at the University of Muenster. Two cycles of ICE or DHAP and rituximab were given. In case of at least a minor response after 2 cycles, 2 additional cycles of the same combination were applied. Response rate, remission duration and duration of survival were evaluated. All 10 patients could be analysed with respect to these endpoints. No treatment related mortality was observed. The response rate (CR/PR) was 60% (10/50%). Twenty percent of the patients had progressive disease. The median duration of remission and survival was 3 and 3.5 months, respectively (range: 1-6 and 1-7 months, respectively), the survival rate was 10%. Eight of 10 patients died because of their underlying disease with short remission duration, 1 patient died of complications of allogeneic transplantation in CR. In conclusion, the combination of platinum-containing chemotherapy (ICE or DHAP) with rituximab demonstrates significant activity in intensively pretreated patients with relapsed or primary refractory diffuse large B-cell lymphoma. Considering the short duration of remission and survival, respectively, other experimental therapeutic approaches (e.g. allogeneic stem cell transplantation, radioimmunotherapy) should be pursued following this treatment in order to induce long-term remission. PMID:14534718

  14. Dose esclation in radioimmunotherapy based on projected whole body dose

    SciTech Connect

    Wahl, R.L.; Kaminski, M.S.; Regan, D.

    1994-05-01

    A variety of approaches have been utilized in conducting phase I radioimmunotherapy dose-escalation trials. Escalation of dose has been based on graded increases in administered mCi; mCi/kg; or mCi/m2. It is also possible to escalate dose based on tracer-projected marrow, blood or whole body radiation dose. We describe our results in performing a dose-escalation trial in patients with non-Hodgkin lymphoma based on escalating administered whole-body radiation dose. The mCi dose administered was based on a patient-individualized tracer projected whole-body dose. 25 patients were entered on the study. RIT with 131 I anti-B-1 was administered to 19 patients. The administered dose was prescribed based on the projected whole body dose, determined from patient-individualized tracer studies performed prior to RIT. Whole body dose estimates were based on the assumption that the patient was an ellipsoid, with 131 antibody kinetics determined using a whole-body probe device acquiring daily conjugate views of 1 minute duration/view. Dose escalation levels proceeded with 10 cGy increments from 25 cGy whole-body and continues, now at 75 cGy. The correlation among potential methods of dose escalation and toxicity was assessed. Whole body radiation dose by probe was strongly correlated with the blood radiation dose determined from sequential blood sampling during tracer studies (r=.87). Blood radiation dose was very weakly correlated with mCi dose (r=.4) and mCi/kg (r=.45). Whole body radiation dose appeared less well-correlated with injected dose in mCi (r=.6), or mCi/kg (r=.64). Toxicity has been infrequent in these patients, but appears related to increasing whole body dose. Non-invasive determination of whole-body radiation dose by gamma probe represents a non-invasive method of estimating blood radiation dose, and thus of estimating bone marrow radiation dose.

  15. Direct dose confirmation of quantitative autoradiography with micro-TLD measurements for radioimmunotherapy

    SciTech Connect

    Griffith, M.H.; Yorke, E.D.; Wessels, B.W.; DeNardo, G.L.; Neacy, W.P.

    1988-11-01

    Autoradiography has shown marked heterogeneous distribution of radioactivity in all ten radiolabeled monoclonal antibody/tumor combinations evaluated by our laboratories for radioimmunotherapy (RIT) in mice. Quantitative autoradiography was performed on two of these combinations (131I-B72.3/colorectal carcinoma and 131I-LYM-1/Raji B-cell lymphoma) to obtain a correlation of film density with radiolabeled antibody distribution. Through the use of sectioned mini-thermoluminescent dosimeter(s) (TLD) or micro-TLD, isodose curves were generated from the film gradient density lines. A computer program was written to compare theoretical absorbed dose calculations to measured micro-TLD values. First-order agreement was reached for both antibody/tumor systems: (a) B72.3/colorectal system--810 cGy measured/824 cGy calculated per 200 microCi injected and (b) LYM-1/lymphoma system--1,740 cGy measured/1,580 cGy calculated per 656 microCi injected (1 cGy = 1 rad). Additionally, the measured absorbed dose heterogeneity over a 500-micron length of up to 400% which suggests that the use of quantitative autoradiography is necessary in order to correctly determine the underlying radiobiological effects of RIT. Theoretical computer modeling based on similar autoradiographic activity distributions has also provided a convenient means of assessing absorbed dose variation patterns from other radiolabels such as 90Y.

  16. Vascular-targeted radioimmunotherapy with the alpha-particle emitter 211At.

    PubMed

    Kennel, S J; Mirzadeh, S; Eckelman, W C; Waldmann, T A; Garmestani, K; Yordanov, A T; Stabin, M G; Brechbiel, M W

    2002-06-01

    Astatine-211, an alpha-particle emitter, was employed in a model system for vascular-targeted radioimmunotherapy of small tumors in mouse lung to compare its performance relative to other radioisotopes in the same system. Astatine-211 was coupled to the lung blood vessel-targeting monoclonal antibody 201B with N-succinimidyl N-(4-[211At]astatophenethyl) succinamate linker. Biodistribution data showed that the conjugate delivered 211At to the lung (260-418% ID/g), where it remained with a biological half-time of about 30 h. BALB/c mice bearing about 100 lung tumor colonies of EMT-6 cells, each about 2000 cells in size, were treated with 211At-labeled monoclonal antibody 201B. The administered activity of 185 kBq per animal extended the life span of treated mice over untreated controls. Injections of 370 kBq, corresponding to an absorbed dose of 25-40 Gy, were necessary to eradicate all of the lung tumors. Mice receiving 740 kBq of 211At-labeled monoclonal antibody 201B developed pulmonary fibrosis 3-4 months after treatment, as did mice treated with 3700 kBq of the alpha-particle emitter 213Bi-labeled monoclonal antibody 201B in previous work. Animals that were injected with 211At bound to untargeted IgG or to glycine, as control agents, also demonstrated therapeutic effects relative to untreated controls. Control groups that received untargeted 211At required about twice as much administered activity for effective therapy as did groups with lung-targeted radioisotope. These results were not consistent with radioisotope biodistribution and dosimetry calculations that indicated that lung-targeted 211At should be at least 10-fold more efficient for lung colony therapy than 211At bound to nontargeting controls. The data showed that 211At is useful for vascular-targeted radioimmunotherapy because lung tumor colonies were eradicated in the mice. Work in this model system demonstrates that vascular targeting of alpha-particle emitters is an efficient therapy for small

  17. Optimizing radioimmunotherapy by matching dose distribution with tumor structure using 3D reconstructions of serial images.

    PubMed

    Flynn, A A; Pedley, R B; Green, A J; Boxer, G M; Boden, R; Begent, R H

    2001-10-01

    The biological effect of radioimmunotherapy (RIT) is most commonly assessed in terms of the absorbed radiation dose. In tumor, conventional dosimetry methods assume a uniform radionuclide and calculate a mean dose throughout the tumor. However, the vasculature of solid tumors tends to be highly irregular and the systemic delivery of antibodies is therefore heterogeneous. Tumor-specific antibodies preferentially localize in the viable, radiosensitive parts of the tumor whereas non-specific antibodies can penetrate into the necrosis where the dose is wasted. As a result, the observed biological effect can be very different to the predicted effect from conventional dose estimates. The purpose of this study is to assess the potential for optimizing the biological effect of RIT by matching the dose-distribution with tumor structure through the selection of appropriate antibodies and radionuclides. Storage phosphor plate technology was used to acquire images of the antibody distribution in serial tumor sections. Images of the distributions of a trivalent (TFM), bivalent (A5B7-IgG), monovalent (MFE-23) and a non-specific antibody (MOPC) were obtained. These images were registered with corresponding images showing tumor morphology. Serial images were reconstructed to form 3D maps of the antibody distribution and tumor structure. Convolution of the image of antibody distribution with beta dose point kernals generated dose-rate distributions for 14C, 131I and 90Y. These were statistically compared with the tumor structure. The highest correlation was obtained for the multivalent antibodies combined with 131I, due to specific retention in viable areas of tumor coupled with the fact that much of the dose was deposted locally. With decreasing avidity the correlation also decreased and with the non-specific antibody this correlation was negative, indicating higher concentrations in the necrotic regions. In conclusion, the dose distribution can be optimized in tumor by selecting

  18. Rapid exacerbation of neuromyelitis optica after rituximab treatment.

    PubMed

    Dai, Yongqiang; Lu, Tingting; Wang, Yuge; Fang, Ling; Li, Rui; Kermode, Allan G; Qiu, Wei

    2016-04-01

    Studies have shown the efficacy of immunosuppressants against neuromyelitis optica (NMO). Rituximab is recommended as an off-label prescription to treat refractory NMO. However, we describe two such patients who were suboptimally responsive to rituximab and whose symptoms worsened after treatment. Our cautionary cases highlight that in a small proportion of patients with refractory NMO, rituximab may either fail or induce rapid relapse of NMO. This suggests we need to consider new treatment strategies for refractory NMO. PMID:26704780

  19. Cancer radioimmunotherapy: Development of an effective approach

    SciTech Connect

    DeNardo, S.J.

    1985-01-01

    The objective of this program is the development of effective approaches for delivering radiation therapy to patients with cancer using radiopharmaceuticals produced from monoclonal antibodies. One major achievement of this program has been the development of a new, Cu-67 chelator (Teta). This chelator firmly holds copper even in the presence of competitive serum proteins. Copper has proven to be labile with other chelators. Also, a single photon emission tomographic camera was purchased with University and philanthropic funds specifically for this program. This allows full-time developmental work on quantitative imaging approaches and in vivo kinetics of our various radiopharmaceutical antibody products. The pharmakinetics of I-123 antibody and antibody fragments have been obtained in patients utilizing quantitative imaging and have demonstrated significant differences as well as the need for long- term studies with I-131 and Cu-67.

  20. Successful radioimmunotherapy of established syngeneic rat colon carcinoma with 211At-mAb

    PubMed Central

    2013-01-01

    Background Most carcinomas are prone to metastasize despite successful treatment of the primary tumor. One way to address this clinical challenge may be targeted therapy with α-emitting radionuclides such as astatine-211 (211At). Radioimmunotherapy utilizing α-particle emitting radionuclides is considered especially suitable for the treatment of small cell clusters and single cells, although lesions of different sizes may also be present in the patient. The aim of this study was primarily to evaluate the toxicity and secondarily in vivo efficacy of a 211At-labeled monoclonal antibody (mAb) directed against colon carcinoma with tumor diameters of approximately 10 mm. Methods Eighteen rats with subperitoneal syngeneic colon carcinoma were allocated to three groups of six animals together with three healthy rats in each group. The groups were injected intravenously with either 150 μg of unlabeled mAbs (controls) or 2.5 or 5 MBq 211At-mAbs directed towards the Lewis Y antigen expressed on the cell membrane of several carcinomas. Tumor volume, body weight, and blood cell counts were monitored for 100 days after treatment. Results Local tumors were non-palpable in five out of six rats after treatment with both activities of 211At-mAbs, compared to one out of six in the control group. At the study end, half of the animals in each group given 211At-BR96 and one animal in the control group were free from disease. Radioimmunotherapy resulted in dose-dependent, transient weight loss and myelotoxicity. Survival was significantly better in the groups receiving targeted alpha therapy than in those receiving unlabeled mAbs. Conclusions This study demonstrates the possibility of treating small, solid colon carcinoma tumors with α-emitting radionuclides such as 211At bound to mAbs, with tolerable toxicity. PMID:23557183

  1. Clinical review: Serious adverse events associated with the use of rituximab - a critical care perspective

    PubMed Central

    2012-01-01

    The advent of biologic agents has provided a more specific and targeted approach to the treatment of various hematological malignancies and other autoimmune disorders. Such biologic agents have been relatively well tolerated with fewer adverse events reported as compared with many other chemotherapeutic agents. Rituximab is a monoclonal antibody to the B-cell marker CD20 and is a common biologic agent widely used for the treatment of B-cell lymphoma, lymphoproliferative disorders, and inflammatory conditions that are refractory to conventional treatment, including rheumatoid arthritis and some vasculitides. However, through randomized controlled trials and post-marketing surveillance, an increasing number of serious adverse events are being associated with the use of rituximab, often leading to or complicating an intensive care unit admission. The purpose of this review is to focus on the severe complications that are associated with the use of rituximab and that require critical care. Management and prevention strategies for the most common complications along with some examples of its uses within the critical care setting are also discussed. PMID:22967460

  2. New insight in the mechanism of action of rituximab: the interferon signature towards personalized medicine.

    PubMed

    Verweij, Cornelis L; Vosslamber, Saskia

    2011-09-01

    Rheumatoid arthritis (RA) is the most common chronic inflammatory disorder of the musculoskeletal system that may cause permanent joint damage. The disease has a major impact on the quality of life of affected individuals, costs for the health care system, and society. Currently, no curative treatment is available, and patients are subjected to a prolonged course of treatment. Due to their role in the pathogenesis of RA, B cells have become an attractive target for therapy. Rituximab (Mabthera®/Rituxan®) is a therapeutic monoclonal antibody against CD20 expressed on B cells, which is effective in depleting B cells and approved worldwide for the treatment of RA. Rituximab was shown to be highly beneficial in decreasing clinical symptoms, safe, and well tolerated. However, clinical experience revealed that approximately 30-40% of RA patients do not respond to it. Given the destructive nature of RA, the risk of adverse effects, and considerable costs for therapy, there is a strong need to make predictions on the clinical outcome before the start of therapy. Since nearly all treated patients experience an effective depletion of circulating B cells, questions have been raised concerning the mechanism of action. In this review, novel developments, in particular the findings on the role of the interferon system, will be highlighted. This may add new and important information to our understanding of the mechanism that underlies the clinical outcome of rituximab treatment and may lead to the identification of biomarkers to predict the response. PMID:21955850

  3. Risk of Reverse Seroconversion of Hepatitis B Virus Surface Antigen in Rituximab-Treated Non-Hodgkin Lymphoma Patients

    PubMed Central

    Hsiao, Liang-Tsai; Chiou, Tzeon-Jye; Gau, Jyh-Pyng; Yang, Ching-Fen; Yu, Yuan-Bin; Liu, Chun-Yu; Liu, Jin-Hwang; Chen, Po-Min; Tzeng, Cheng-Hwai; Chan, Yu-Jiun; Yang, Muh-Hwa; Huang, Yi-Hsiang

    2015-01-01

    Abstract Rituximab causes hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-seronegative patients with CD20-positive B-cell non-Hodgkin lymphoma (CD20+ NHL), especially for those seropositive to the antibody of core antigen (anti-HBc). Clinical hepatitis usually develops after reverse seroconversion of HBsAg (HBV-RS), indicated by the reappearance of HBsAg in serum. Because of the relatively high prevalence of anti-HBc seropositivity in unvaccinated HBsAg-seronegative adults in an HBV hyperendemic area, we aimed to investigate additional factors influencing the development of rituximab-associated HBV-RS. Between January 2000 and December 2010, unvaccinated HBsAg-seronegative adults with CD20+ NHL who had received rituximab-containing therapy but not anti-HBV agents were enrolled. Patients with and without HBV-RS were compared in terms of clinical factors and treatments including the number of cycles of rituximab therapy, and transplantation. Competing risk regression was used to identify the factors associated with HBV-RS. For the 482 patients enrolled, the serological status of anti-HBc was available in 75.9%, with a seropositivity rate of 86.6%. At the last follow-up, a total of 33 (6.85%) patients had HBV-RS, with 95.8% anti-HBc seropositive, 78.9% anti-HBs seropositive, and none anti-HCV seropositive. HBV-RS patients have received more cycles (≥6) and prolonged durations of rituximab therapy, and hematopoietic stem cell transplantation. The overall survival was not different between patients with and those without HBV-RS. At the time of HBV-RS, a total of 25 (78.1%) patients had hepatitis flare, especially when HBV-RS appeared during/after induction therapy (100%, 10 of 10). Three (9.1%) patients had fulminant hepatitis, resulting in death in 1 (3%) patient. A higher rituximab cycle intensity was associated with a higher rate of hepatitis flare at the time of HBV-RS. When death in the absence of HBV-RS was considered as the competing risk

  4. GD2-targeted immunotherapy and radioimmunotherapy

    PubMed Central

    Dobrenkov, Konstantin; Cheung, Nai-Kong

    2014-01-01

    Ganglioside GD2 is a tumor-associated surface antigen found in a broad spectrum of human cancers and stem cells. They include pediatric embryonal tumors (neuroblastoma, retinoblastoma, brain tumors, osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma), as well as adult cancers (small cell lung cancer, melanoma, soft tissue sarcomas). Because of its restricted normal tissue distribution, GD2 has been proven safe for antibody targeting. Anti-GD2 antibody is now incorporated into the standard of care for the treatment of high risk metastatic neuroblastoma. Building on this experience, novel combinations of antibody, cytokines, cells and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In the review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions. PMID:25440605

  5. Macrodosimetry and microdosimetry in radioimmunotherapy. Final report, July 15, 1989 -- July 14, 1992

    SciTech Connect

    Leichner, P.K.

    1991-12-01

    This report summarizes research in beta-particle dosimetry, quantitative single-photon emission computed tomography (SPECT), the clinical implementation of these two areas of research in radioimmunotherapy (RIT), and postgraduate training provided since the inception of this grant on July 15, 1989. To improve beta-particle dosimetry, a point source function was developed that is valid for a wide range of beta emitters. Analytical solutions for beta-particle dose rates within out outside slabs of finite thickness were validated in experimental tumors and are now being used in clinical RIT. Quantitative SPECT based on the circular harmonic transform (CHT) algorithm was validated in phantom, experimental, and clinical studies. This has led to improved macrodosimetry in clinical RIT. In dosimetry at the multi-cellular level studies were made of the HepG2 human hepatoblastoma grown subcutaneously in nude mice. Histologic sections and autoradiographs were prepared to quantitate activity distributions of radiolabeled antibodies. Absorbed-dose calculations are being carried out for {sup 131}I and {sup 90}Y beta particles for these antibody distributions.

  6. Optimising the therapeutic ratio of radioimmunotherapy; an investigation of the roles of chimerisation, fractionation and radiation dosimetry

    NASA Astrophysics Data System (ADS)

    Violet, John Albert

    2007-12-01

    Radioimmunotherapy (RIT) is a targeted form of treatment for cancer which uses tumour-associated antibodies to selectively deliver a therapeutic radionuclide to sites of disease. In lymphoma, radioimmunotherapy has proved a remarkably effective agent due to the high radiosensitivity of the tumour and its propensity to undergo apoptosis following irradiation. However, success in the treatment of the more radioresistant common solid tumours has been less successful, and for these patients RIT remains investigative. The effectiveness of RIT is limited by non-specific irradiation of normal tissues whilst antibody remains in the circulation, in particular bone marrow, and also by immunogenicity of antibody which does not allow for repeated therapy. In the first chapter I have hypothesised that lymphomas expressing the interleukin-2 receptor might be effectively treated using a radiolabeled antibody to this receptor. In a phase I/II clinical study, 131I labelled CHT-25, a chimeric antibody against the IL-2Ra chain, has shown encouraging evidence of efficacy in the 9 patients with multiply- relapsed lymphomas treated so far. In addition, use of this antibody has been associated with low immunogenicity allowing for repeated therapies to be given. In the second chapter I have hypothesised that dosimetry led, individual patient therapy, might further optimise 1311 CHT-25 treatment. To investigate this I have used marrow toxicity as a biological assay of absorbed dose and shown that simple, but individual, patient biodistribution indices correlate better with observed toxicity than the population-based dose estimates currently employed. I have proposed that adoption of individual patient dosimetry using tracer studies is worthy of further investigation for the future development of 131I- CHT-25. In the third chapter I have hypothesised that dose fractionation might improve the therapeutic ratio of RIT. This has been investigated in a pre-clinical human colorectal xenograft

  7. Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia.

    PubMed

    Burkhardt, Birgit; Yavuz, Deniz; Zimmermann, Martin; Schieferstein, Jutta; Kabickova, Edita; Attarbaschi, Andishe; Lisfeld, Jasmin; Reiter, Alfred; Makarova, Olga; Worch, Jennifer; Bonn, Bettina R; Damm-Welk, Christine

    2016-09-01

    Recent studies in adult lymphoma patients have indicated a correlation between polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and the response to rituximab treatment. In vitro, cells expressing FcγRIIIa-158V mediate antibody-dependent cellular cytotoxicity (ADCC) more efficiently than cells expressing FcγRIIIa-158F. The impact of the FCGR2A-131HR polymorphism is unclear. In this study, the FCGR polymorphisms FCGR3A-158VF and FCGR2A-131HR were analyzed in pediatric patients with mature aggressive B cell non-Hodgkin lymphoma/leukemia (B-NHL). Pediatric patients received a single dose of rituximab monotherapy. Response was evaluated on day 5 followed by standard chemotherapy for B-NHL. Among 105 evaluable patients, a response to rituximab was observed in 21 % of those homozygous for FcγRIIa-131RR (5/24) compared to 48 % of patients who were HH and HR FcγRIIa-131 allele carriers (18/34 and 21/47, respectively; p = 0.044). Among patients with the FCGR3A-158 polymorphism, those homozygous for the FF genotype had a significantly favorable rituximab response rate of 59 % (22/37) compared to 32 % in patients who were FcγRIIIa-158VV and FcγRIIIa-VF allele carriers (2/9 and 20/59, respectively; p = 0.022). A stringent phase II response evaluation of children and adolescents with B-NHL after one dose of rituximab monotherapy showed a significant association between the rituximab response rate and FCGR polymorphisms. These findings support the hypothesis that FCGR polymorphisms represent patient-specific parameters that influence the response to rituximab. PMID:27376362

  8. [Cold agglutinin disease -  no response to glucocorticoids and rituximab, what treatment is best for the 3rd line of therapy? Case report and review of the literature].

    PubMed

    Adam, Z; Pejchalová, A; Chlupová, G; Ríhová, L; Pour, L; Krejčí, M; Cervinek, L; Král, Z; Mayer, J

    2013-09-01

    Acquired autoimmune haemolytic anaemia is divided according to the characteristics of immunoglobulin causing haemolysis. The most frequent are haemolytic anaemia with thermal antibodies. They bind to erythrocytes and initiate their destruction in the reticuloendothelial system cells, leading to extravascular haemolysis. Cold agglutinin disease differs significantly from haemolytic anaemia with thermal antibodies. Agglutination is caused by monoclonal antibodies, in most cases class IgM and very rarely class IgG. Under cold conditions they bind to erythrocytes and cause their agglutination and subsequent disorder of blood circulation in body parts with a lower temperature. Agglutinins binding initiate the binding of the complement to the erythrocytes. Under warm conditions the binding becomes loose but the parts of the complement, which are already bound, cause haemolysis, which is mainly of an intravascular nature. The loose haemoglobin causes haemoglobinuria. Description of a patient with the disease. The 1st symptoms of the disease, i.e. anaemia + circulatory disorders in the acral parts of the body, disappearing under warm conditions followed with haemoglobinuria, led to the dia-gnosis of cold agglutinin disease. The 1st line treatment, prednison, did not show any response. The 2nd line treatment used was rituximab and dexametazon. Rituximab was administered in doses of 500 mg/ m2 to 4 times in a row in weekly intervals. Dexametazon was administered in doses of 40 mg from 1st to 4th day and from 15th to 18th day of the cycle. This treatment, however, did not show any response either. Therefore this article brings an overview of all publications regarding the disease treatment with the aim of choosing the most effective treatment options in the case of failure of the monotherapy using rituximab. The 1st line treatment for cold agglutinin disease is rituximab in monotherapy, usually administered once per week at least for 4 weeks. This treatment shows a response

  9. Radioimmunotherapy treatment planning based on radiation absorbed dose or patient size

    SciTech Connect

    Eary, J.F.; Krohn, K.A.; Press, O.W. |

    1996-05-01

    Several approaches have been used to plan treatment doses for patients undergoing radioimmunotherapy. Investigators often use fixed doses, or doses based on patient size (mCi/kg or mCi/m{sup 2}). Our treatment protocols for lymphoma and leukemia involved calculation of tissue radiation absorbed dose based on images from a trace labeled infusion of antibody prior to treatment. In a recent analysis of patients treated in the Phase I and II dose escalation trial for treatment of non-Hodgkin`s lymphoma with I-131 anti-CD20 antibody (B1), we investigated the relationship between our dosimetry based treatment and dose based on patient size. Tissue radiation dose for several normal organs and for tumors were plotted versus the mCi administered per kg or m{sup 2} of the patient to evaluate the relationship between the two treatment approaches. These graphs showed correlation coefficients ranging from 0.021 to 0.684, demonstrating the variability in antibody catabolism between patients. This means that fixed doses or administrations based on patient size do not deliver consistent radiation doses to normal organs or tumors. This finding was extrapolated to show that toxicity from doses based on patient size di not correlate with treatment dose; those based on calculated rad/organ did. Phase I clinical trials using treatment doses based on patient size where there are likely to be variations in patient antibody catabolism will result in confounding toxicities at apparently similar mCi dose levels. Use of pre-treatment scans for treatment dose planning are worth the additional effort by normalizing the normal tissue toxicity.

  10. Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia.

    PubMed

    Maury, Sébastien; Chevret, Sylvie; Thomas, Xavier; Heim, Dominik; Leguay, Thibaut; Huguet, Françoise; Chevallier, Patrice; Hunault, Mathilde; Boissel, Nicolas; Escoffre-Barbe, Martine; Hess, Urs; Vey, Norbert; Pignon, Jean-Michel; Braun, Thorsten; Marolleau, Jean-Pierre; Cahn, Jean-Yves; Chalandon, Yves; Lhéritier, Véronique; Beldjord, Kheira; Béné, Marie C; Ifrah, Norbert; Dombret, Hervé

    2016-09-15

    Background Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial. Methods We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. Results From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group. Conclusions Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .). PMID:27626518

  11. IMPACT OF PRE-TRANSPLANT RITUXIMAB ON SURVIVAL AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR DIFFUSE LARGE B-CELL LYMPHOMA

    PubMed Central

    Fenske, Timothy S.; Hari, Parameswaran N.; Carreras, Jeanette; Zhang, Mei-Jie; Kamble, Rammurti T.; Bolwell, Brian J.; Cairo, Mitchell S.; Champlin, Richard E.; Chen, Yi-Bin; Freytes, César O.; Gale, Robert Peter; Hale, Gregory A.; Ilhan, Osman; Khoury, H. Jean; Lister, John; Maharaj, Dipnarine; Marks, David I.; Munker, Reinhold; Pecora, Andrew L.; Rowlings, Philip A.; Shea, Thomas C.; Stiff, Patrick; Wiernik, Peter H.; Winter, Jane N.; Rizzo, J. Douglas; van Besien, Koen; Lazarus, Hillard M.; Vose, Julie M.

    2010-01-01

    Incorporation of the anti-CD20 monoclonal antibody rituximab into front-line regimens for diffuse large B-cell lymphoma (DLBCL) has resulted in improved survival. Despite this progress, many patients develop refractory or recurrent DLBCL and then receive autologous hematopoietic stem cell transplantation (AuHCT). It is unclear to what extent pre-transplant exposure to rituximab affects outcomes following AuHCT. Outcomes of 994 patients receiving AuHCT for DLBCL between 1996 and 2003 were analyzed according to whether rituximab was (n=176, “+R” group) or was not (n=818, “ −R” group) administered with front-line or salvage therapy prior to AuHCT. The +R group had superior progression-free survival (50% versus 38%, p=0.008) and overall survival (57% versus 45%, p=0.006) at 3 years. Platelet and neutrophil engraftment were not affected by exposure to rituximab. Non-relapse mortality (NRM) did not differ significantly between the +R and −R groups. In multivariate analysis, the +R group had improved progression-free survival (relative risk of relapse/progression or death 0.64, p<0.001) and improved overall survival (relative risk of death of 0.74, p=0.039). We conclude that pre-transplant rituximab is associated with a lower rate of progression and improved survival following AuHCT for DLBCL, with no evidence of impaired engraftment or increased NRM. PMID:19822306

  12. Timing determines dexamethasone and rituximab induced synergistic cell death.

    PubMed

    Adem, Jemal; Eray, Mine; Eeva, Jonna; Nuutinen, Ulla; Pelkonen, Jukka

    2016-07-01

    Dysregulation of cell death signaling pathways in many cell types such as B lymphocytes (B-cells) can lead to cancer, for example to B-cell lymphomas. Rituximab (RTX) and glucocorticoids such as dexamethasone (Dex) are widely used to treat hematological malignancies including B-cell lymphomas. Although the combination of Dex and RTX improves the treatment outcome of lymphoma patients, most lymphomas remain incurable diseases. Therefore, a detailed investigation of Dex- and RTX-induced signaling might provide new insights into the therapeutic benefits of these drugs. In this paper, we describe Dex- and RTX-induced signaling pathways and their downstream target proteins/cells. In addition, we also overview how the signaling initiated by Dex and RTX modulate the outcome of Dex- and RTX-mediated cell death in lymphoma cells. The combination of Dex and RTX results in massive cell death in lymphoma cells. However, pretreatment of lymphoma cells or mononuclear cytotoxic cells with Dex followed by RTX leads to a decrease in apoptosis or it impairs antibody-dependent cellular cytotoxicity (ADCC). RTX-mediated ADCC is impaired by Dex-induced depletion of cytotoxic cells, whereas RTX-mediated short-term ERK1/2 activation decreases Dex-induced apoptosis. Therefore, the timing of the combination of Dex and RTX is a determining factor for the synergistic effect of these cell death inducing agents. PMID:27290654

  13. Depletion of B‐Cells With Rituximab Improves Endothelial Function and Reduces Inflammation Among Individuals With Rheumatoid Arthritis

    PubMed Central

    Hsue, Priscilla Y.; Scherzer, Rebecca; Grunfeld, Carl; Imboden, John; Wu, Yuaner; del Puerto, Gus; Nitta, Elaine; Shigenaga, Judy; Schnell Heringer, Amanda; Ganz, Peter; Graf, Jonathan

    2014-01-01

    Background Individuals with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, partly due to systemic inflammation and endothelial dysfunction. B‐cells play an important pathogenic role in the inflammatory process that drives RA disease activity. Rituximab, a chimeric murine/human monoclonal antibody that depletes B‐cells, is an effective therapy for RA. The purpose of this study was to determine whether B‐cell depletion with rituximab reduces systemic inflammation and improves macrovascular (brachial artery flow‐mediated dilation, FMD) and microvascular (reactive hyperemia) endothelial function in RA patients. Methods and Results RA patients received a single course of rituximab (1000 mg IV infusion at baseline and on day 15). FMD, reactive hyperemia, inflammatory markers, and clinical assessments were performed at baseline, week 12, and week 24. Twenty patients (95% female, median age 54 years) completed the study. Following treatment, FMD improved from a baseline of 4.5±0.4% to 6.4±0.6% at 12 weeks (mean±SE; P<0.0001), followed by a decline at week 24; a similar pattern was observed for hyperemic velocity. Significant decreases in RA disease scores, high‐sensitivity C‐reactive protein, erythrocyte sedimentation rate, and circulating CD19+ B‐cells were sustained through week 24. Cholesterol and triglycerides became significantly although modestly elevated during the study. Conclusions Depletion of B‐cells with rituximab improved macrovascular and microvascular endothelial function and reduced systemic inflammation, despite modest elevation in lipids. Given these results, rituximab should be evaluated in the future for its possible role in reducing excess cardiovascular risk in RA. Clinical Trial Registration URL http://ClinicalTrials.gov. Unique identifier: NCT00844714. PMID:25336464

  14. Therapeutic effectiveness of rituximab in a patient with unresponsive autoimmune pulmonary alveolar proteinosis.

    PubMed

    Amital, Anat; Dux, Shlomo; Shitrit, David; Shpilberg, Ofer; Kramer, Mordechai R

    2010-11-01

    Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterised by the accumulation of lung surfactant in the alveoli. In most cases it is an autoimmune disease with antibodies directed against the growth factor granulocyte-macrophage colony stimulating factor (GM-CSF). Standard of care consists of whole lung lavages in symptomatic patients. An alternative treatment is GM-CSF injections. The case history is reported of a patient with PAP and severe dyspnoea and hypoxaemia. Whole lung lavages and GM-CSF initially resulted in partial remission. However, the patient's condition deteriorated and her saturation during rest with high-flow oxygen treatment was 85%. The patient was treated with an anti-CD20 antibody rituximab which resulted in dramatic improvement. Room air saturation increased to 98% with exercise and she no longer required supplemental oxygen. The diffusion capacity for carbon monoxide increased from 27% to 48% of predicted and the chest x-rays improved. Rituximab may be useful in the treatment of patients with unresponsive PAP. PMID:20855439

  15. Complex cell geometry and sources distribution model for Monte Carlo single cell dosimetry with iodine 125 radioimmunotherapy

    NASA Astrophysics Data System (ADS)

    Arnaud, F. X.; Paillas, S.; Pouget, J. P.; Incerti, S.; Bardiès, M.; Bordage, M. C.

    2016-01-01

    In cellular dosimetry, common assumptions consider concentric spheres for nucleus and cell and uniform radionuclides distribution. These approximations do not reflect reality, specially in the situation of radioimmunotherapy with Auger emitters, where very short-ranged electrons induce hyper localised energy deposition. A realistic cellular dosimetric model was generated to give account of the real geometry and activity distribution, for non-internalizing and internalizing antibodies (mAbs) labelled with Auger emitter I-125. The impact of geometry was studied by comparing the real geometry obtained from confocal microscopy for both cell and nucleus with volume equivalent concentric spheres. Non-uniform and uniform source distributions were considered for each mAbs distribution. Comparisons in terms of mean deposited energy per decay, energy deposition spectra and energy-volume histograms were calculated using Geant4. We conclude that realistic models are needed, especially when energy deposition is highly non-homogeneous due to source distribution.

  16. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis

    PubMed Central

    Fornoni, Alessia; Sageshima, Junichiro; Wei, Changli; Merscher-Gomez, Sandra; Robier, Aguillon-Prada; Jauregui, Alexandra N.; Li, Jing; Mattiazzi, Adela; Ciancio, Gaetano; Chen, Linda; Zilleruelo, Gaston; Abitbol, Carolyn; Chandar, Jayanthi; Seeherunvong, Wacheree; Ricordi, Camillo; Ikehata, Masami; Rastaldi, Maria Pia; Reiser, Jochen; Burke, George W.

    2013-01-01

    Focal segmental glomerulosclerosis (FSGS) is a prevalent glomerular disease characterized by proteinuria, progression to end stage renal disease and recurrence of proteinuria after kidney transplantation in approximately one third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab recognizes CD20 on B-lymphocytes but might also bind sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL-3b) and regulates acid-sphyngomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. Incidence of nephrotic-range proteinuria and change in estimated glomerular filtration rate (ΔeGFR) were analyzed. SMPDL-3b immunostaining was performed in post-reperfusion kidney biopsies. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of post-transplant proteinuria and decreased ΔeGFR. The number of SMPDL-3b+ podocytes in post-reperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase downregulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Either SMPDL-3b overexpression or treatment with rituximab prevented disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where the gene encoding SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b–dependent manner. PMID:21632984

  17. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis.

    PubMed

    Fornoni, Alessia; Sageshima, Junichiro; Wei, Changli; Merscher-Gomez, Sandra; Aguillon-Prada, Robier; Jauregui, Alexandra N; Li, Jing; Mattiazzi, Adela; Ciancio, Gaetano; Chen, Linda; Zilleruelo, Gaston; Abitbol, Carolyn; Chandar, Jayanthi; Seeherunvong, Wacheree; Ricordi, Camillo; Ikehata, Masami; Rastaldi, Maria Pia; Reiser, Jochen; Burke, George W

    2011-06-01

    Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of posttransplant proteinuria and stabilization of glomerular filtration rate. The number of SMPDL-3b(+) podocytes in postreperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase down-regulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner. PMID:21632984

  18. Granulomatosis with polyangiitis (Wegener's granulomatosis) with hard palate and bronchial perforations treated with rituximab - a case report.

    PubMed

    Kosałka, Joanna; Bazan-Socha, Stanisława; Zugaj, Anna; Ignacak, Maria; Zuk, Joanna; Sokołowska, Barbara; Musiał, Jacek

    2014-01-01

    We present a case of a 57-year-old woman suffering from granulomatosis with polyangiitis (GPA), who in the seventh months of immunosuppressive treatment (cyclophosphamide) progressed with new pulmonary changes and perforations of the hard palate and bronchi. Rituximab was introduced resulting in B-cell depletion and disappearance of anti-PR3 antibody. Palatal holes have substantially diminished and all bronchial perforations disappeared, covered by fibrous tissue. In the fourth month after rituximab administration, large scarring obstruction of the right main bronchus with upper and middle lobes atelectasis emerged. Because of increasing dyspnoea, stenotic bronchus was re-opened by bronchoscopy. Intervention was complicated by bilateral pneumothorax and later, on the seventh day, by fatal pulmonary bleeding. To our knowledge, this is the first report of GPA refractory to cyclophosphamide complicated by palatal and bronchial perforations. PMID:25133814

  19. An update on the evidence for the efficacy and safety of rituximab in the management of neuromyelitis optica

    PubMed Central

    Collongues, Nicolas; de Seze, Jérôme

    2016-01-01

    Neuromyelitis optica spectrum disorders (NMOSDs) is a new concept which includes classical neuromyelitis optica (NMO) and partial forms of NMO such as recurrent optic neuritis with positive aquaporin-4 antibodies (AQP4) or brainstem symptoms (intractable hiccups or vomiting). This disease is clearly distinguished from multiple sclerosis (MS) and the therapeutic approach is clearly different. Rituximab is actually considered to be one of the most efficient treatments of NMOSD, even if class I studies are clearly lacking. In the present review, we describe the state of the art about rituximab treatment in NMOSD, including adults and children, plus its efficacy and tolerance and we also underline the questions that should be addressed in the near future. PMID:27134673

  20. An update on the evidence for the efficacy and safety of rituximab in the management of neuromyelitis optica.

    PubMed

    Collongues, Nicolas; de Seze, Jérôme

    2016-05-01

    Neuromyelitis optica spectrum disorders (NMOSDs) is a new concept which includes classical neuromyelitis optica (NMO) and partial forms of NMO such as recurrent optic neuritis with positive aquaporin-4 antibodies (AQP4) or brainstem symptoms (intractable hiccups or vomiting). This disease is clearly distinguished from multiple sclerosis (MS) and the therapeutic approach is clearly different. Rituximab is actually considered to be one of the most efficient treatments of NMOSD, even if class I studies are clearly lacking. In the present review, we describe the state of the art about rituximab treatment in NMOSD, including adults and children, plus its efficacy and tolerance and we also underline the questions that should be addressed in the near future. PMID:27134673

  1. Improvement of paraneoplastic limbic encephalitis after systemic treatment with rituximab in a patient with B-cell chronic lymphocytic leukemia.

    PubMed

    Nogai, Hendrik; Israel-Willner, Heike; Zschenderlein, Rolf; Pezzutto, Antonio

    2013-01-01

    Limbic encephalitis is an inflammatory disease of the central nervous system characterized by diverse neurologic symptoms including mnestic disturbances, hallucinations, and seizures as well as behavioral symptoms like depression, personality changes, and acute confusional states resembling dementia. Several antibodies have been described in the pathogenesis of limbic encephalitis. It is often a paraneoplastic syndrome associated with small cell lung cancer, breast cancer, or Hodgkin's lymphoma among others. Here, we report a patient with B-cell chronic lymphocytic leukemia (B-CLL), presenting with otherwise unexplained neurologic symptoms consistent with limbic encephalitis. Despite intensive diagnostic procedures, no causing agent could be identified. Pleocytosis consisting of T cells was detected in the cerebrospinal fluid (CSF). We initiated anti-B-cell therapy with Rituximab for B-CLL with quick and durable resolution of symptoms. We speculate that disruption of interaction between autoreactive T and malignant B cells is responsible for the therapeutic effect of Rituximab. PMID:23984126

  2. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment

    PubMed Central

    Fluge, Øystein; Risa, Kristin; Lunde, Sigrid; Alme, Kine; Rekeland, Ingrid Gurvin; Sapkota, Dipak; Kristoffersen, Einar Kleboe; Sørland, Kari; Bruland, Ove; Dahl, Olav; Mella, Olav

    2015-01-01

    Background Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS. Methods In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months. Findings Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8–66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity. Conclusion In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed

  3. Cost-effectiveness of rituximab in refractory cold agglutinin disease.

    PubMed

    Panwar, U; Mathews, C; Cullis, J O

    2008-08-01

    Cold haemagglutinin disease (CHAD) is an uncommon condition frequently associated with B-cell lymphoproliferative disorders and is refractory to conventional treatments used in autoimmune haemolytic anaemia. Rituximab has been used in this condition with favourable and lasting responses. Cost has been a major limitation to its use in such indication. We present cost-effectiveness analysis of the use of rituximab in two patients with CHAD. Rituximab successfully controlled haemolysis in both cases of CHAD and was found to be cost-effective through reducing transfusion needs. PMID:18665831

  4. Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder

    PubMed Central

    Nosadini, Margherita; Alper, Gulay; Riney, Catherine J.; Benson, Leslie A.; Mohammad, Shekeeb S.; Ramanathan, Sudarshini; Nolan, Melinda; Appleton, Richard; Leventer, Richard J.; Deiva, Kumaran; Brilot, Fabienne; Gorman, Mark P.; Waldman, Amy T.; Banwell, Brenda

    2016-01-01

    Objective: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. Methods: Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as “repopulation,” “depletion,” or “depletion failure” relapses (repopulation threshold CD19 ≥10 × 106 cells/L). Results: The 16 patients (14 girls; mean age 9.6 years, range 1.8–15.3) had a mean of 6.1 events (range 1–11) during a mean follow-up of 6.1 years (range 1.6–13.6) and received a total of 76 rituximab courses (mean 4.7, range 2–9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 “repopulation,” 3 “depletion,” and 4 “depletion failure” relapses. Of the 13 “repopulation” relapses, 4 had CD19 10–50 × 106 cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. Conclusion: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. Classification of evidence: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation

  5. Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial.

    PubMed

    Wiseman, Gregory A; Gordon, Leo I; Multani, Pratik S; Witzig, Thomas E; Spies, Stewart; Bartlett, Nancy L; Schilder, Russell J; Murray, James L; Saleh, Mansoor; Allen, Roberta S; Grillo-López, Antonio J; White, Christine A

    2002-06-15

    Mildly thrombocytopenic patients with relapsed or refractory low-grade non-Hodgkin lymphoma (NHL) have an increased risk of chemotherapy-induced myelosuppression following treatment. The safety and efficacy of radioimmunotherapy with a reduced dose of (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]; maximum 32 mCi [1.2 GBq]) was evaluated in 30 patients with mild thrombocytopenia (100-149 x 10(9) platelets/L) who had advanced, relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. The ibritumomab tiuxetan regimen included an infusion of rituximab (250 mg/m(2)) and injection of (111)In ibritumomab tiuxetan (5 mCi [185 MBq]) for dosimetry evaluation, followed 1 week later with rituximab (250 mg/m(2)) and (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]). Patients (median age, 61 years; 90% stage III/IV at study entry; 83% follicular lymphoma; and 67% with bone marrow involvement) had a median of 2 prior therapy regimens (range, 1-9). Estimated radiation-absorbed doses were well below the study-defined maximum allowable for all 30 patients. With the use of the International Workshop criteria for NHL response assessment, the overall response rate was 83% (37% complete response, 6.7% complete response unconfirmed, and 40% partial response). Kaplan-Meier estimated median time to progression (TTP) was 9.4 months (range, 1.7-24.6). In responders, Kaplan-Meier estimated median TTP was 12.6 months (range, 4.9-24.6), with 35% of data censored. Toxicity was primarily hematologic, transient, and reversible. The incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 33%, 13%, and 3%, respectively. Reduced-dose ibritumomab tiuxetan is safe and well tolerated and has significant clinical activity in this patient population. PMID:12036859

  6. Collection of hematopoietic stem cells after previous radioimmunotherapy is feasible and does not impair engraftment after autologous stem cell transplantation in follicular lymphoma.

    PubMed

    Derenzini, Enrico; Stefoni, Vittorio; Maglie, Roberto; Casadei, Beatrice; Pellegrini, Cinzia; Broccoli, Alessandro; Stefani, Giulia; Fanti, Stefano; Motta, Maria Rosa; Narducci, Riccardo; Argnani, Lisa; Zinzani, Pier Luigi

    2013-12-01

    Major concerns about radioimmunotherapy (RIT) administration early in the course of follicular lymphoma (FL) are long-term toxicity and the theoretical impairment of hematopoietic stem cell (HSC) harvest, but few data are available about mobilization rates after RIT. This study evaluates the impact of prior therapy with RIT (yttrium-90 ibritumomab tiuxetan) and different chemotherapy regimens in all FL patients (N = 103) attempting HSC mobilization at our institution over the last 7 years. Sixty-nine patients received R-CHOP (rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone) or CHOP-like regimens, 21 patients received R-FM (rituximab-fludarabine-mitoxantrone), and 13 patients received RIT before HSC mobilization. Median CD34+ cell yield at first mobilization was 7.2 × 10(6)/kg in the R-CHOP group versus 4.3 in the R-FM group versus 1.7 in the RIT group (P = .02 R-CHOP versus R-FM; P < .0001 R-CHOP versus RIT; P < .02 R-FM versus RIT). Although 8 of 13 patients initially failed to collect enough HSC after RIT, a second and/or salvage harvest was successfully performed in 7 patients, with 10 of 13 patients (77%) finally undergoing autologous stem cell transplantation (ASCT). No differences in engraftment kinetics were observed between the three groups (R-CHOP versus R-FM versus RIT). Although mobilization was significantly impaired in patients previously treated with RIT, a salvage HSC harvest and ASCT after RIT were safe and feasible in most patients. PMID:24055654

  7. Development of dosimetric approaches to treatment planning for radioimmunotherapy. Annual report 1989--1990

    SciTech Connect

    DeNardo, S.J.

    1990-12-31

    The objective of quantitative imaging is to provide pharmacokinetic information for patients that is analogous to that provided by biodistribution studies in mice. Radionuclide images depict the distribution of labeled antibodies in-vivo; thus the amount of radionuclide in a specific organ or site can be estimated by relating the counts detected in a defined region of interest to the total radionuclide content. This pharmacokinetic information can be used to obtain definitive and relevant answers to basic questions of importance for optimizing radioimmunoimaging and radioimmunotherapy and, in addition, can provide a data base from which to calculate the distribution of radiation absorbed doses. The research employs quantitative imaging in evaluating therapies. Quantitative imaging is performed by a certified nuclear medicine technician using the Siemens gamma camera interfaced with the microVAX II. The technician processes the imaging data and obtains pharmacokinetic information from it using programs developed by the authors and others. A large amount of data has been acquired and analyzed on the pharmacokinetics, dosimetry and toxicity of radiolabeled monoclonal therapy. Important dosimetry data on the whole body, marrow and tumor doses are available and all studies are archived so that they can be retrospectively analyzed. Although the radiation absorbed doses delivered to tumor sites were modest, significant biological responses were found.

  8. Development of dosimetric approaches to treatment planning for radioimmunotherapy. DOE annual report

    SciTech Connect

    1998-05-01

    The objective of quantitative imaging is to Provide pharmacokinetic information for patients that is analogous to that provided by biodistribution studies in mice. Radio nuclide images depict the distribution of labeled antibodies in-vivo; thus the amount of radio nuclide in a specific organ or site can be estimated by relating the counts detected in a defined region of interest to the total radio nuclide content. This pharmacokinetic information can be used to obtain definitive and relevant answers to basic questions of importance for optimizing radioimmunoimaging and radioimmunotherapy and, in addition, can provide a data base from which to calculate the distribution of radiation absorbed doses. The projects supported by this program routinely employ quantitative imaging in evaluating therapies. Quantitative imaging is performed by a certified nuclear medicine technician using the Siemens gamma camera interfaced with the microVAX II. The technician processes the imaging data and obtains pharmacokinetic information from it using programs developed by us and others. During this grant period project staff have acquired and analyzed a large amount of data on the pharmacokinetics, dosimetry and toxicity of radiolabeled monoclonal therapy. Important dosimetry data on the whole body, marrow and tumor doses are available and all studies are archived so that they can be retrospectively analyzed.

  9. Naive and radiolabeled antibodies to E6 and E7 HPV-16 oncoproteins show pronounced antitumor activity in experimental cervical cancer

    PubMed Central

    Phaëton, R; Gutierrez, J; Jiang, Z; Karabakhtsian, RG; Albanese, J; Sunkara, J; Fisher, DR; Goldberg, GL; Dadachova, E

    2015-01-01

    Background In spite of profound reduction in incidence, cervical cancer claims >275,000 lives annually. Previously we demonstrated efficacy and safety of radioimmunotherapy directed at HPV16 E6 oncoprotein in experimental cervical cancer. Materials & methods We undertook a direct comparison of targeting E7 and E6 oncoproteins with specific 188Rhenium-labeled monoclonal antibodies in CasKi subcutaneous xenografts of cervical cancer cells in mice. Results The most significant tumor inhibition was seen in radioimmunotherapy-treated mice, followed by the unlabeled monoclonal antibodies to E6 and E7. No hematological toxicity was observed. Immunohistochemistry suggests that the effect of unlabeled antibodies is C3 complement mediated. Conclusion We have demonstrated for the first time that radioimmunotherapy directed toward E7 oncoprotein inhibits experimental tumors growth, decreases E7 expression and may offer a novel approach to cervical cancer therapy. PMID:26098137

  10. Radiolabeled antibodies for therapy of infectious diseases

    PubMed Central

    Dadachova, Ekaterina; Casadevall, Arturo

    2014-01-01

    Novel approaches to treatment of infectious diseases are urgently needed. This need has resulted in renewing the interest in antibodies for therapy of infectious diseases. Radioimmunotherapy (RIT) is a cancer treatment modality, which utilizes radiolabeled monoclonal antibodies (mAbs). During the last decade we have translated RIT into the field of experimental fungal, bacterial and HIV infections. In addition, successful proof of principle experiments with radiolabeled pan-antibodies that bind to antigens shared by major pathogenic fungi were performed in vitro. The armamentarium of pan-antibodies would result in reducing the dependence on microorganism-specific antibodies and thus would speed up the development of RIT of infections. We believe that the time is ripe for deploying RIT into the clinic to combat infectious diseases. PMID:25599011

  11. Chlorambucil-rituximab as first-line therapy in patients affected by follicular non-Hodgkin's lymphoma: a retrospective single-centre study.

    PubMed

    Martinelli, Giovanni; Montoro, Juan; Vanazzi, Anna; Andreola, Giovanna; Liptrott, Sarah; Radice, Davide; Negri, Mara; Preda, Lorenzo; Pruneri, Giancarlo; Laszlo, Daniele

    2015-12-01

    Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has been shown to be active in newly diagnosed and relapsed patients with follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. Many studies suggest that the prognosis of patients with FL may improve when it is used in combination with chemotherapy. Despite these advances, the disease remains essentially incurable with standard therapy, and novel approaches to treatment are needed because optimal therapy is not defined. The combination of chlorambucil-rituximab is one of several standard treatment options for FL. Here, we considered data arising from 75 patients with newly diagnosed FL at the European Institute of Oncology treated with the combination of rituximab plus chlorambucil. The aim of this study was to evaluate the efficacy and safety of chlorambucil and rituximab, delivered 6 mg/m(2) /day orally for 6 weeks and 375 mg/m(2) in a standard 4-weekly schedule, respectively. Patients responding to the induction therapy received a prolonged therapy with four additional cycles of chlorambucil plus rituximab. Seventy-one patients (94.6%) completed the treatment; four patients discontinued treatment because of grade 3-4 hematological toxicity. The overall response rate was 97.3% including 74.7% of complete responses. Only two patients had a stable disease at revaluation after treatment. With a median follow-up of 57 months, 72 patients (96%) are alive. Median event-free survival (EFS) and median overall survival (OS) were not reached; 5-year OS rate was 98.4%. The 5-year EFS was 71.3%. By univariate and multivariate analyses, elevated beta-2 microglobulin levels and partial responses to therapy were correlated with worse EFS. These results suggest that the combination of chlorambucil and rituximab is an active and safe regimen in patients with newly diagnosed FL, principally in those with low tumour burden and favourable prognostic factors. PMID

  12. Screening for viral hepatitis prior to rituximab chemotherapy.

    PubMed

    Leonard, A N; Love, B L; Norris, L B; Siddiqui, S K; Wallam, M N; Bennett, C L

    2016-01-01

    In 2008, the CDC published guidelines recommending screening of all persons undergoing treatment with rituximab to identify persons at risk of hepatitis B virus (HBV) reactivation. We evaluated implementation of this recommendation in veterans, who are at increased risk of HBV, and determined characteristics of those screened. We also evaluated a control setting, rates of hepatitis C virus (HCV) screening among the same rituximab-treated patients. There are no guidelines that recommend HCV screening prior to initiation of rituximab. Medical records of patients receiving rituximab between January 2006 and December 2012 were reviewed according to two time periods: 2006-2008 (period 1, pre-guidelines) and 2009-2012 (period 2, post-guidelines). Patient demographics, concomitant chemotherapy regimen (protocol, dose, duration), treatment indication, risk factors for hepatitis infection (substance abuse, homelessness, human immunodeficiency virus (HIV)), and HBV/HCV screening status were documented. During the study period, 102 patients were treated with rituximab (49 in period 1 and 53 in period 2). During periods 1 and 2, 22 and 32 % of rituximab-treated patients were screened for HBV, respectively (p = 0.375). Treatment during 2009 was the only significant predictor of HBV screening in the adjusted model (p = 0.01). For HCV during periods 1 and 2, 22 and 21 % of patients were screened, respectively (p = 1.00). There were no significant predictors of HCV screening. Rates of screening for HBV among rituximab-treated patients were low, both before and after dissemination of guidelines recommending universal HBV screening of rituximab-treated patients. PMID:26382277

  13. Rituximab therapy in nephrotic syndrome due to AH amyloidosis.

    PubMed

    Katoh, Nagaaki; Matsuda, Masayuki; Miyazaki, Daigo; Gono, Takahisa; Yazaki, Masahide; Ikeda, Shu-Ichi

    2009-01-01

    We report a patient with AH amyloidosis associated with lymphoplasmacytic leukemia that has remained in a stable state with a nephrotic syndrome for 17 months since the commencement of cyclic rituximab therapy aimed at suppression of pathogenetic gamma heavy chains. Free light chains in serum and CD20-positive cells in peripheral blood were useful as hematological markers in the patient. Rituximab might be a potent therapeutic option for AH amyloidosis associated with a B-cell lymphoproliferative disorder. PMID:19590993

  14. A review of monoclonal antibody therapies in lymphoma.

    PubMed

    Teo, Esmeralda Chi-yuan; Chew, Yveline; Phipps, Colin

    2016-01-01

    Monoclonal antibodies (moAb) represent a novel way of delivering therapy through specific target antigens expressed on lymphoma cells and minimizes the collateral damage that is common with conventional chemotherapy. The paradigm of this approach is the targeting of CD20 by rituximab. Since its FDA approval in 1997, rituximab has become the standard of care in almost every line of therapy in most B-cell lymphomas. This review will briefly highlight some of the key rituximab trials while looking more closely at the evidence that is bringing other antibodies, including next generation anti-CD20 moAbs, and anti-CD30 moAbs, among others to the forefront of lymphoma therapy. PMID:26318093

  15. Modern trends in radioimmunotherapy of cancer: pretargeting strategies for the treatment of ovarian cancer.

    PubMed

    McQuarrie, S A; Xiao, Z; Miller, G G; Mercer, J R; Suresh, M R

    2001-06-01

    A review of published data on some of the problems associated in treating cancer using radioimmunotherapy is presented. Potential improvements for this type of therapy using pretargeting strategies are discussed and preliminary results on a novel multistep regimen to treat human ovarian cancer are presented. A pretargeting strategy using a biotinylated, anti-CA125 monoclonal antibody (MAb) to attract biotinylated long-circulating liposomes to the surface of CA125-expressing ovarian cancer cells, was employed. Confocal laser scanning microscopy and fluorescent labels were used to establish the biodistribution patterns in NIH:OVCAR-3 (CA-125 positive) and SK-OV-3 (CA-125 negative) human ovarian cancer cells. Shedding kinetics of the pretargeted stage were measured using 125I labeled MAbs. No significant internalization of the MAb used in the pretargeting step was observed by 4 hrs. The antibody was gradually internalized starting at 6 hrs, and most of the labelled MAb was detected in cytoplasm by 24 hrs. Shedding and exocytosis of the antigen-MAb complex was not significant for up to 6-hours following administration of the iodinated MAb. Biotinylated liposomes were shown to specifically target the biotinylated MAb/streptavidin complex on the cell surface. We have demonstrated that by a three-step pretargeting approach, biotinylated liposomes can be specifically delivered to cells pretargeted with biotinylated MAb/SAv complex. The slow internalization and shedding properties of the two MAbs are ideal for multistep pretargeting methods. A successful multistep linkage was established with the biotinylated MAb B27.1, streptavidin and biotinylated liposomes to OVCAR-3 cells, but not to SK-OV-3 cells. PMID:11476165

  16. Preparation and preclinical evaluation of humanised A33 immunoconjugates for radioimmunotherapy.

    PubMed Central

    King, D. J.; Antoniw, P.; Owens, R. J.; Adair, J. R.; Haines, A. M.; Farnsworth, A. P.; Finney, H.; Lawson, A. D.; Lyons, A.; Baker, T. S.

    1995-01-01

    A humanised IgG1/k version of A33 (hA33) has been constructed and expressed with yields up to 700 mg l-1 in mouse myeloma NS0 cells in suspension culture. The equilibrium dissociation constant of hA33 (KD = 1.3 nM) was shown to be equivalent to that of the murine antibody in a cell-binding assay. hA33 labelled with yttrium-90 using the macrocyclic chelator 12N4 (DOTA) was shown to localise very effectively to human colon tumour xenografts in nude mice, with tumour levels increasing as blood concentration fell up to 144 h. A Fab' variant of hA33 with a single hinge thiol group to facilitate chemical cross-linking has also been constructed and expressed with yields of 500 mg l-1. Trimaleimide cross-linkers have been used to produce a trivalent Fab fragment (hA33 TFM) that binds antigen on tumour cells with greater avidity than hA33 IgG. Cross-linkers incorporating 12N4 or 9N3 macrocycles have been used to produce hA33 TFM labelled stably and site specifically with yttrium-90 or indium-111 respectively. These molecules have been used to demonstrate that hA33 TFM is cleared more rapidly than hA33 IgG from the circulation of animals but does not lead to accumulation of these metallic radionuclides in the kidney. 90Y-labelled hA33 TFM therefore appears to be the optimal form of the antibody for radioimmunotherapy of colorectal carcinoma. Images Figure 3 PMID:8519646

  17. Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    PubMed Central

    Frost, Sofia H. L.; Frayo, Shani L.; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark D.; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; Bäck, Tom A.; Fisher, Darrell R.; Press, Oliver W.

    2015-01-01

    Purpose Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice. Methods Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibody-streptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. Results The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTA-biotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes. Conclusion 90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in

  18. Therapeutic antibodies against cancer

    PubMed Central

    Adler, Mark J.; Dimitrov, Dimiter S.

    2012-01-01

    Antibody-based therapeutics against cancer are highly successful in clinic and currently enjoy unprecedented recognition of their potential; 13 monoclonal antibodies (mAbs) have been approved for clinical use in the European Union and in the United States (one, mylotarg, was withdrawn from market in 2010). Three of the mAbs (bevacizumab, rituximab, trastuzumab) are in the top six selling protein therapeutics with sales in 2010 of more than $5 bln each. Hundreds of mAbs including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small molecule drugs and mAbs with optimized pharmacokinetics are in clinical trials. However, challenges remain and it appears that deeper understanding of mechanisms is needed to overcome major problems including resistance to therapy, access to targets, complexity of biological systems and individual variations. PMID:22520975

  19. Validated LC/MS Bioanalysis of Rituximab CDR Peptides Using Nano-surface and Molecular-Orientation Limited (nSMOL) Proteolysis.

    PubMed

    Iwamoto, Noriko; Takanashi, Megumi; Hamada, Akinobu; Shimada, Takashi

    2016-07-01

    Presently, monoclonal antibodies (mAbs) therapeutics have big global sales and are starting to receive competition from biosimilars. We previously reported that the nano-surface and molecular-orientation limited (nSMOL) proteolysis which is optimal method for bioanalysis of antibody drugs in plasma. The nSMOL is a Fab-selective limited proteolysis, which utilize the difference of protease nanoparticle diameter (200 nm) and antibody resin pore diameter (100 nm). In this report, we have demonstrated that the full validation for chimeric antibody Rituximab bioanalysis in human plasma using nSMOL proteolysis. The immunoglobulin fraction was collected using Protein A resin from plasma, which was then followed by the nSMOL proteolysis using the FG nanoparticle-immobilized trypsin under a nondenaturing condition at 50°C for 6 h. After removal of resin and nanoparticles, Rituximab signature peptides (GLEWIGAIYPGNGDTSYNQK, ASGYTFTSYNMHWVK, and FSGSGSGTSYSLTISR) including complementarity-determining region (CDR) and internal standard P14R were simultaneously quantified by multiple reaction monitoring (MRM). This quantification of Rituximab using nSMOL proteolysis showed lower limit of quantification (LLOQ) of 0.586 µg/mL and linearity of 0.586 to 300 µg/mL. The intra- and inter-assay precision of LLOQ, low quality control (LQC), middle quality control (MQC), and high quality control (HQC) was 5.45-12.9% and 11.8, 5.77-8.84% and 9.22, 2.58-6.39 and 6.48%, and 2.69-7.29 and 4.77%, respectively. These results indicate that nSMOL can be applied to clinical pharmacokinetics study of Rituximab, based on the precise analysis. PMID:27150271

  20. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wang, Xuemei; O'Brien, Susan M.; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Lerner, Susan; Kantarjian, Hagop

    2011-01-01

    Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes. PMID:21670470

  1. Lymphomatoid granulomatosis treated successfully with rituximab in a renal transplant patient.

    PubMed

    Castrale, Cindy; El Haggan, Wael; Chapon, Françoise; Reman, Oumedaly; Lobbedez, Thierry; Ryckelynck, Jean Philippe; Hurault de Ligny, Bruno

    2011-01-01

    Lymphomatoid granulomatosis (LYG) in renal transplant recipients is rare multisystemic angiocentric lymphoproliferative disorder with significant malignant potential. Here, we describe LYG in a 70-year-old renal allograft recipient who, 4 years after transplantation, on tacrolimus and mycophenolate mofetil and prednisone maintenance immunosuppression, complained of low-grade fever, persistent headache and gait disturbance. The MRI of the brain revealed diffuse periventricular cerebral and cerebellar contrast-enhanced lesions. The CT scan of the thorax showed multiple pulmonary nodular opacities in both lung fields. The patient was diagnosed LYG based on the cerebral biopsy showing perivascular infiltration of CD20-positive B-lymphocytes with granulomatous lesions and immunofluorescence staining with anti-EBV antibodies. With careful reduction of the immunossuppression combined with the use of rituximab, our patient showed a complete disappearance of LYG, and she is clinically well more than 4 years after the diagnosis, with good kidney function. No recurrence has been observed by radiological imaging until now. This is the first report of a durable (>4 years) complete remission of LYG after treatment with rituximab in renal transplantation. PMID:21559262

  2. Neuromyelitis optica: Contribution of therapeutic responses markers monitoring in patients given rituximab.

    PubMed

    Romero, G; Ticchioni, M; Cohen, M; Rosenthal-Allieri, M A; Mondot, L; Lebrun Frenay, C

    2016-03-01

    Neuromyelitis optica (NMO) is a central nervous system inflammatory autoimmune disease characterized by medullary and/or optical nerve damage. It is rare but life-threatening. Concerning the treatment of NMO, many drugs have been used in background therapy. Some studies have shown efficacy of rituximab (an antiCD20 monoclonal anti-body) either on the reduction of the annual number of exacerbation or the mean score EDSS. In 2013, a Korean team reported a new protocol during which they administered rituximab only when memory B lymphocytes CD27+ were detectable in the bloodstream. In our patient, institution of this protocol led to clinical benefit with a major decrease in the EDSS score over time (7 in August 2012 vs. 1 in October 2015), a reduction of the total administered dose (4g in 2013 vs. 1.375g in 2014 vs. 0g in 2015) and side effects. Compared with the rate of theoretical administration, health expenditure savings reached 1700 Euros per month over the 11-month treatment. Monitoring therapeutic response markers with memory B lymphocyte counts appear to be an efficient cost-effective way to measure clinical efficiency, reduce total doses, and limit side effects. PMID:26915311

  3. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma

    PubMed Central

    Ruan, Jia; Martin, Peter; Shah, Bijal; Schuster, Stephen J.; Smith, Sonali M.; Furman, Richard R.; Christos, Paul; Rodriguez, Amelyn; Svoboda, Jakub; Lewis, Jessica; Katz, Orel; Coleman, Morton; Leonard, John P.

    2015-01-01

    BACKGROUND Mantle-cell lymphoma is generally incurable. Initial treatment is not standardized but usually includes cytotoxic chemotherapy. Lenalidomide, an immunomodulatory compound, and rituximab, an anti-CD20 antibody, are active in patients with recurrent mantle-cell lymphoma. We evaluated lenalidomide plus rituximab as a first-line therapy. METHODS We conducted a single-group, multicenter, phase 2 study with induction and maintenance phases. During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles; the dose was escalated to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle and was reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression. The primary end point was the overall response rate. Secondary end points included outcomes related to safety, survival, and quality of life. RESULTS A total of 38 participants were enrolled at four centers from July 2011 through April 2014. The median age was 65 years. On the basis of the Mantle Cell Lymphoma International Prognostic Index scores, the proportions of participants with low-risk, intermediate-risk, and high-risk disease at baseline were similar (34%, 34%, and 32%, respectively). The most common grade 3 or 4 adverse events were neutropenia (in 50% of the patients), rash (in 29%), thrombocytopenia (in 13%), an inflammatory syndrome (“tumor flare”) (in 11%), anemia (in 11%), serum sickness (in 8%), and fatigue (in 8%). At the median follow-up of 30 months (through February 2015), the overall response rate among the participants who could be evaluated was 92% (95% confidence interval [CI], 78 to 98), and the complete response rate was 64% (95% CI, 46 to 79); median progression-free survival had not been reached. The 2-year progression-free survival was estimated to be

  4. Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia

    PubMed Central

    Cheson, Bruce D.; Pagel, John M.; Hillmen, Peter; Barrientos, Jacqueline C.; Zelenetz, Andrew D.; Kipps, Thomas J.; Flinn, Ian; Ghia, Paolo; Eradat, Herbert; Ervin, Thomas; Lamanna, Nicole; Coiffier, Bertrand; Pettitt, Andrew R.; Ma, Shuo; Stilgenbauer, Stephan; Cramer, Paula; Aiello, Maria; Johnson, Dave M.; Miller, Langdon L.; Li, Daniel; Jahn, Thomas M.; Dansey, Roger D.; Hallek, Michael; O’Brien, Susan M.

    2014-01-01

    BACKGROUND Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemo-therapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta iso-form of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemo-therapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.) PMID:24450857

  5. Radiolabelling rituximab with (99m)Tc in three steps procedure.

    PubMed

    Fontan, Charlotte; Bezombes, Christine; Salabert, Anne Sophie; Costes, Julien; Lopez, Raphael; Fournie, Jean-Jacques; Avet-Loiseau, Hervé; Coulais, Yvon; Payoux, Pierre; Tafani, Mathieu

    2015-06-15

    Lymphomas are the most frequent haematological malignancy. In non-Hodgkin's lymphomas (NHL), more than 90% of tumor cells express the cluster of differentiation (CD) 20 antigen. At the end of frontline therapy, the evaluation of remission is based on computed tomography (CT) and positron emission tomography coupled with computer tomography (PET/CT) with [(18)F]-fluorodeoxyglucose ([(18)F]FDG). Unfortunately, these techniques are not specific and cannot distinguish residual active tumor from inflammation. The aim of this study was to develop a specific radiotracer of NHL CD 20+ cells for clinical applications. The radiolabelling technique presented, based on the use of tricarbonyl compound, does not include an antibody reduction because this step could damage the protein. Actually, rituximab, an anti-CD 20 chimeric antibody used for the treatment of these NHL, was radiolabelled with Isolink® (99m)Tc-tricarbonyl compound in a three-step procedure without using a specific antibody reducer. Radiolabelling yield was greater than 97%. In vitro experiments showed a conservation of antibody integrity. In vivo experiments using Single-photon emission computed tomography/CT showed significant tumor targeting 24 h after injection of the radiotracer. It was consequently possible to develop an immunoradiolabelling method to specifically detect the residual disease. As this procedure is fast, reproducible and gentle, it will be possible to comply with Good Manufacturing Practices. PMID:26017396

  6. Analysing saturable antibody binding based on serum data and pharmacokinetic modelling

    NASA Astrophysics Data System (ADS)

    Kletting, Peter; Kiryakos, Hady; Reske, Sven N.; Glatting, Gerhard

    2011-01-01

    In radioimmunotherapy, organ dose calculations are frequently based on pretherapeutic biodistribution measurements, assuming equivalence between pretherapeutic and therapeutic biodistribution. However, when saturation of antibody binding sites is important, this assumption might not be justified. Residual antibody and different amounts of administered antibody may lead to a considerably altered therapeutic biodistribution. In this study we developed a method based on serum activity measurements to investigate this effect in radioimmunotherapy with 90Y-labelled anti-CD66 antibody. Pretherapeutic and therapeutic serum activity data of ten patients with acute leukaemia were fitted to a set of four parsimonious pharmacokinetic models. All models included the key mechanisms of antibody binding, immunoreactivity and degradation; however, they differed with respect to linear or nonlinear binding and global or individual fitting of the model parameters. The empirically most supported model was chosen according to the corrected Akaike information criterion. The nonlinear models were most supported by the data (sum of probabilities ≈100%). Using the presented method, we identified relevant saturable binding for radioimmunotherapy with 90Y-labelled anti-CD66 antibody solely based on serum data. This general method may also be applicable to investigate other systems where saturation of binding sites might be important.

  7. Is rituximab sub-optimally dosed in indolent B cell lymphoma?

    PubMed

    Sawalha, Yazeed; Rouphail, Basel; Jia, Xuefei; Dean, Robert M; Hill, Brian T; Jagadeesh, Deepa; Pohlman, Brad L; Smith, Mitchell R

    2016-09-01

    Rituximab pharmacokinetics are affected by gender, age and weight and can affect outcomes in aggressive B cell lymphoma. Less is known about the pharmacokinetics of rituximab in indolent B cell lymphoma (iNHL). We analysed the effects of gender, age, weight and body surface area on the outcomes of 303 patients treated with first line rituximab-based regimens for iNHL. The patients were divided into 3 treatment cohorts: rituximab only, rituximab + chemotherapy (R-CTX) and R-CTX followed by rituximab maintenance; furthermore, each cohort was subdivided as follicular (FL) or non-FL, based on histology. Older males and patients with higher weight had worse outcomes when treated with R-CTX, probably due to faster rituximab clearance. Our results concur with studies of R-CTX for DLBCL. As this effect was not observed in patients treated with rituximab alone or R-CTX followed by rituximab maintenance, we hypothesize that higher rituximab levels reached with weekly rituximab and/or prolonged exposure achieved with maintenance therapy exceed the therapeutic threshold, even with faster clearance, which nullifies the negative effect of higher weight and male gender. In conclusion, under current practices, a subset of patients with iNHL, i.e., FL treated with R-CTX, may be sub-optimally dosed with rituximab. PMID:27136331

  8. Radioimmunotherapy with radioactive nanoparticles: Biological doses and treatment efficiency for vascularized tumors with or without a central hypoxic area

    SciTech Connect

    Bouchat, V.; Nuttens, V. E.; Michiels, C.; and others

    2010-04-15

    Purpose: Radioactive atoms attached to monoclonal antibodies are used in radioimmunotherapy to treat cancer while limiting radiation to healthy tissues. One limitation of this method is that only one radioactive atom is linked to each antibody and the deposited dose is often insufficient to eradicate solid and radioresistant tumors. In a previous study, simulations with the Monte Carlo N-Particle eXtended code showed that physical doses up to 50 Gy can be delivered inside tumors by replacing the single radionuclide by a radioactive nanoparticle of 5 nm diameter containing hundreds of radioactive atoms. However, tumoral and normal tissues are not equally sensitive to radiation, and previous works did not take account the biological effects such as cellular repair processes or the presence of less radiosensitive cells such as hypoxic cells. Methods: The idea is to adapt the linear-quadratic expression to the tumor model and to determine biological effective doses (BEDs) delivered through and around a tumor. This BED is then incorporated into a Poisson formula to determine the shell control probability (SCP) which predicts the cell cluster-killing efficiency at different distances ''r'' from the center of the tumor. BED and SCP models are used to analyze the advantages of injecting radioactive nanoparticles instead of a single radionuclide per vector in radioimmunotherapy. Results: Calculations of BED and SCP for different distances r from the center of a solid tumor, using the non-small-cell lung cancer as an example, were investigated for {sup 90}Y{sub 2} O{sub 3} nanoparticles. With a total activity of about 3.5 and 20 MBq for tumor radii of 0.5 and 1.0 cm, respectively, results show that a very high BED is deposited in the well oxygenated part of the spherical carcinoma. Conclusions: For either small or large solid tumors, BED and SCP calculations highlight the important benefit in replacing the single {beta}-emitter {sup 90}Y attached to each antibody by a {sup

  9. Successful use of rituximab in refractory idiopathic thrombocytopenic purpura in a patient with common variable immunodeficiency.

    PubMed

    Al-Ahmad, M; Al-Rasheed, M; Al-Muhani, A

    2010-01-01

    Idiopathic thrombocytopenic purpura (ITP) is a common autoimmune disease in patients with common variable immunodeficiency (CVID). We describe a 36-year-old woman with CVID. The clinical course of her disease was complicated by bronchiectasis, antiphospholipid antibody syndrome, and portal vein thrombosis. She developed recurrent attacks of ITP refractory to high doses of corticosteroid, intravenous immunoglobulin (IVIG), and splenectomy. She received a total of 5 doses of rituximab (375 mg/m2) and achieved an immediate and persistent response. Therapy was well tolerated. Her platelet count remained above 370,000/microL for 8 months of follow-up, despite repeated infections. During this period the patient remained off corticosteroids and on continuous IVIG replacement therapy. PMID:20635793

  10. 90-yttrium-ibritumomab tiuxetan consolidation of fludarabine, mitoxantrone, rituximab in intermediate/high-risk follicular lymphoma: updated long-term results after a median follow-up of 7 years.

    PubMed

    Casadei, Beatrice; Pellegrini, Cinzia; Pulsoni, Alessandro; Annechini, Giorgia; De Renzo, Amalia; Stefoni, Vittorio; Broccoli, Alessandro; Gandolfi, Letizia; Quirini, Federica; Tonialini, Lorenzo; Morigi, Alice; Argnani, Lisa; Zinzani, Pier Luigi

    2016-06-01

    Radioimmunotherapy (RIT) after an induction phase with conventional chemoimmunotherapy became an attractive strategy of consolidation for patients with advanced follicular lymphoma: in particular, in many studies RIT was represented by yttrium-90-ibritumomab tiuxetan ((90) Y-IT). Independently by the different front-line treatment, updates on the long-term follow-up of these studies are needed because the disease course of follicular lymphoma is characterised by multiple relapses and progressively shorter durations of response. We report updated long-term efficacy and toxicity results of a multicenter phase II study on sequential treatment with four cycles of fludarabine, mitoxantrone, and rituximab followed by (90) Y-IT as front-line therapy for untreated patients with intermediate/high-risk follicular lymphoma. With a median follow-up of 84 months, only 19/49 (38.8%) complete response patients relapsed, yielding an estimated long-term disease-free survival of 62.6%. The 7-year overall survival was 72.7%. Four (7.3%) second acute myeloid leukemia occurred, with a median time following RIT of 42 months. A relevant patients' responsiveness to subsequent therapies occurred: approximately 65% of relapsed patients obtained a good clinical response after the second-line treatment. These data represented the first evidence of a real role even in the long period of 90Y-IT after a fludarabine-containing regimen plus rituximab in the treatment of high-risk follicular lymphoma. PMID:26990782

  11. Alpha imaging confirmed efficient targeting of CD45-positive cells after astatine-211 (211At)-radioimmunotherapy for hematopoietic cell transplantation

    PubMed Central

    Frost, Sofia H.L.; Miller, Brian W.; Bäck, Tom A.; Santos, Erlinda B.; Hamlin, Donald K.; Knoblaugh, Sue E.; Frayo, Shani L.; Kenoyer, Aimee L.; Storb, Rainer; Press, Oliver W.; Wilbur, D. Scott; Pagel, John M.; Sandmaier, Brenda M.

    2015-01-01

    Alpha-radioimmunotherapy targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-211 (211At)-radioimmunotherapy, extending the analysis to include intra-organ 211At activity distribution and α-imaging-based small-scale dosimetry, along with immunohistochemical staining. Methods Eight normal dogs were injected with either 0.75 (n=5) or 1.00 mg/kg (n=3) of 211At-B10-CA12.10C12 (11.5–27.6 MBq/kg). Two were euthanized and necropsied 19–22 hours post injection (p.i.), and six received autologous HCT three days after 211At-radioimmunotherapy, following lymph node and bone marrow biopsies at 2–4 and/or 19 hours p.i. Blood was sampled to study toxicity and clearance; CD45 targeting was evaluated by flow cytometry. 211At localization and small-scale dosimetry were assessed using two α-imaging systems: α-camera and iQID. Results Uptake of 211At was highest in spleen (0.31–0.61 %IA/g), lymph nodes (0.02–0.16 %IA/g), liver (0.11–0.12 %IA/g), and marrow (0.06–0.08 %IA/g). Lymphocytes in blood and marrow were efficiently targeted using either MAb dose. Lymph nodes remained unsaturated, but displayed targeted 211At localization in T lymphocyte-rich areas. Absorbed doses to blood, marrow, and lymph nodes were estimated at 3.1, 2.4, and 3.4 Gy/166 MBq, respectively. All transplanted dogs experienced transient hepatic toxicity. Liver enzyme levels were temporarily elevated in 5 of 6 dogs; 1 treated with 1.00 mg MAb/kg developed ascites and was euthanized 136 days after HCT. Conclusion 211At-anti-CD45 radioimmunotherapy with 0.75 mg MAb/kg efficiently targeted blood and marrow without severe toxicity. Dosimetry calculations and observed radiation-induced effects indicated that sufficient 211At-B10-CA12.10C12 localization was achieved for efficient conditioning for HCT. PMID:26338894

  12. (211)At-labeled and biotinylated effector molecules for pretargeted radioimmunotherapy using poly-L- and poly-D-Lysine as multicarriers.

    PubMed

    Lindegren, Sture; Karlsson, Börje; Jacobsson, Lars; Andersson, Håkan; Hultborn, Ragnar; Skarnemark, Gunnar

    2003-09-01

    Poly-L- and poly-D-lysine were evaluated as carriers of astatine and biotin for prospective use as effector molecules in pretargeted radioimmunotherapy of micrometastases. The precursor polylysine was derivatized in a three-step, single-pot procedure, including biotinylation with biotin amidocaproic N-hydroxysuccinimide, astatination via the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate, and, finally, charge modification using succinic anhydride. The chemistry was shown to be very facile, with a biotinylation efficiency of 75 +/- 5%, and overall radiochemical yields in the range of 50-70%. After charge modification, no amines could be detected in the final product. The biotin function was unaffected by the chemistry and the radiation, as confirmed by almost complete binding of the effector molecule to avidin beads using a convenient filter tube assay. The effector molecules were evaluated in tumor-free female nude mice with regard to whole-body retention and tissue distribution after i.p. administration. The distribution of the L-isomer effector molecule showed rapid whole-body clearance with low uptake in all tissues, whereas the D-isoform showed whole-body clearance related to uptake in the kidneys. Both D-isomer and L-isomer showed faster blood clearance and generally lower tissue uptakes than labeled antibodies. The normal tissue distribution after the peritoneal administration implies that pretargeting using L-structure polylysine as the effector molecule may give a higher therapeutic index than that achieved in conventional radioimmunotherapy. PMID:14506185

  13. Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies.

    PubMed

    Duong, Minh Ngoc; Matera, Eva-Laure; Mathé, Doriane; Evesque, Anne; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles

    2015-01-01

    Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated. PMID:25523586

  14. Antagonistic human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo.

    PubMed

    Roghanian, Ali; Teige, Ingrid; Mårtensson, Linda; Cox, Kerry L; Kovacek, Mathilda; Ljungars, Anne; Mattson, Jenny; Sundberg, Annika; Vaughan, Andrew T; Shah, Vallari; Smyth, Neil R; Sheth, Bhavwanti; Chan, H T Claude; Li, Zhan-Chun; Williams, Emily L; Manfredi, Giusi; Oldham, Robert J; Mockridge, C Ian; James, Sonya A; Dahal, Lekh N; Hussain, Khiyam; Nilsson, Björn; Verbeek, J Sjef; Juliusson, Gunnar; Hansson, Markus; Jerkeman, Mats; Johnson, Peter W M; Davies, Andrew; Beers, Stephen A; Glennie, Martin J; Frendéus, Björn; Cragg, Mark S

    2015-04-13

    Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment. PMID:25873171

  15. A preclinical model of CD38-pretargeted radioimmunotherapy for plasma cell malignancies

    PubMed Central

    Green, Damian J.; Orgun, Nural N.; Jones, Jon C.; Hylarides, Mark D.; Pagel, John M.; Hamlin, Donald K.; Wilbur, D.S.; Lin, Yukang; Fisher, Darrell R.; Kenoyer, Aimee L.; Frayo, Shani L.; Gopal, Ajay K.; Orozco, Johnnie J.; Gooley, Theodore A.; Wood, Brent L.; Bensinger, William I.; Press, Oliver W.

    2014-01-01

    The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma (MM) has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on plasma cell malignancies. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin-biotin pretargeted RIT (PRIT) directed against the CD38 antigen, were assessed as approaches to deliver radiation doses sufficient for MM cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24hr after PRIT, while ratios never exceeded 1:1 with conventional RIT. 90Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 µCi to 1200 µCi of anti-CD38 pretargeted 90Y-DOTA-biotin, including 100% complete remissions (no detectable tumor in treated mice compared to tumors that were 2982±2834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 µCi of anti-CD38 pretargeted 90Y-DOTA-biotin achieved long-term myeloma-free survival (>70 days) compared to none (0%) of the control animals. PMID:24371230

  16. Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment.

    PubMed

    Orozco, Johnnie J; Kenoyer, Aimee; Balkin, Ethan R; Gooley, Ted A; Hamlin, Donald K; Wilbur, D Scott; Hylarides, Mark D; Frost, Sofia H L; Mawad, Raya; O'Donnell, Paul; Sandmaier, Brenda M; Fuchs, Ephraim J; Luznik, Leo; Green, Damian J; Gopal, Ajay K; Press, Oliver W; Pagel, John M

    2016-01-21

    Many patients with hematologic malignancies cannot tolerate hematopoietic cell transplantation (HCT), whereas others may not have a compatible human leukocyte antigen-matched donor. To overcome these limitations, we optimized a conditioning regimen employing anti-CD45 radioimmunotherapy (RIT) replacing total body irradiation (TBI) before haploidentical HCT in a murine model. Mice received 200 to 400 μCi (90)Y-anti-CD45 antibody (30F11), with or without fludarabine (5 days starting day -8), with cyclophosphamide (CY; days -2 and +2) for graft-versus-host disease prophylaxis, and 1.5 × 10(7) haploidentical donor bone marrow cells (day 0). Haploidentical bone marrow transplantation (BMT) with 300 μCi (90)Y-anti-CD45 RIT and CY, without TBI or fludarabine, led to mixed chimeras with 81.3 ± 10.6% mean donor origin CD8(+) cells detected 1 month after BMT, and remained stable (85.5 ± 11% mean donor origin CD8(+) cells) 6 months after haploidentical BMT. High chimerism levels were induced across multiple hematopoietic lineages 28 days after haploidentical BMT with 69.3 ± 14.1%, 75.6 ± 20.2%, and 88.5 ± 11.8% CD3(+) T cells, B220(+) B cells, and CD11b(+) myeloid cells, respectively. Fifty percent of SJL leukemia-bearing mice treated with 400 μCi (90)Y-DOTA-30F11, CY, and haploidentical BMT were cured and lived >200 days. Mice treated with 200 μCi (90)Y-DOTA-30F11 had a median overall survival of 73 days, while untreated leukemic mice had a median overall survival of 34 days (P < .001, Mantel-Cox test). RIT-mediated haploidentical BMT without TBI may increase treatment options for aggressive hematologic malignancies. PMID:26576864

  17. A preclinical model of CD38-pretargeted radioimmunotherapy for plasma cell malignancies.

    PubMed

    Green, Damian J; Orgun, Nural N; Jones, Jon C; Hylarides, Mark D; Pagel, John M; Hamlin, Donald K; Wilbur, D S; Lin, Yukang; Fisher, Darrell R; Kenoyer, Aimee L; Frayo, Shani L; Gopal, Ajay K; Orozco, Johnnie J; Gooley, Theodore A; Wood, Brent L; Bensinger, William I; Press, Oliver W

    2014-02-15

    The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on malignant plasma cells. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin-biotin pretargeted RIT (PRIT) directed against the CD38 antigen were assessed as approaches to deliver radiation doses sufficient for multiple myeloma cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24 hours after PRIT, whereas ratios never exceeded 1:1 with conventional RIT. (90)Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 to 1,200 μCi of anti-CD38 pretargeted (90)Y-DOTA-biotin, including 100% complete remissions (no detectable tumor in treated mice compared with tumors that were 2,982% ± 2,834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 μCi of anti-CD38 pretargeted (90)Y-DOTA-biotin achieved long-term myeloma-free survival (>70 days) compared with none (0%) of the control animals. PMID:24371230

  18. Combining α-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction.

    PubMed

    Ménager, Jérémie; Gorin, Jean-Baptiste; Maurel, Catherine; Drujont, Lucile; Gouard, Sébastien; Louvet, Cédric; Chérel, Michel; Faivre-Chauvet, Alain; Morgenstern, Alfred; Bruchertseifer, Frank; Davodeau, François; Gaschet, Joëlle; Guilloux, Yannick

    2015-01-01

    Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT) is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. α-Radioimmunotherapy (α-RIT) is a type of internal radiotherapy which is currently under development to treat disseminated tumors. α-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of α-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining α-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA). Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells). We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established. PMID:26098691

  19. Combining α-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction

    PubMed Central

    Ménager, Jérémie; Gorin, Jean-Baptiste; Maurel, Catherine; Drujont, Lucile; Gouard, Sébastien; Louvet, Cédric; Chérel, Michel; Faivre-Chauvet, Alain; Morgenstern, Alfred; Bruchertseifer, Frank; Davodeau, François

    2015-01-01

    Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT) is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. α-Radioimmunotherapy (α-RIT) is a type of internal radiotherapy which is currently under development to treat disseminated tumors. α-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of α-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining α-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA). Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells). We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established. PMID:26098691

  20. Rituximab in combination with multiagent chemotherapy for pediatric follicular lymphoma.

    PubMed

    Kumar, Riten; Galardy, Paul J; Dogan, Ahmet; Rodriguez, Vilmarie; Khan, Shakila P

    2011-08-01

    Given the rarity of follicular lymphoma (FL) in children, there is limited data on which to base treatment recommendations. Herein, we report our institutional experience of using rituximab with multiagent chemotherapy for pediatric FL. Six pediatric patients were diagnosed with FL from 2000 to 2009. All patients received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for varying durations. Five of the six patients remain in remission with a median follow-up of 31 months. Larger randomized trials are indicated to establish the efficacy of this regimen for pediatric FL patients. PMID:21462303

  1. Association of rituximab with graphene oxide confers direct cytotoxicity for CD20-positive lymphoma cells

    PubMed Central

    Luo, Chengke; Deng, Zhenghao; Li, Lan; Clayton, Frederic; Chen, Alexander L.; Wei, Ran; Miles, Rodney; Stephens, Deborah M.; Glenn, Martha; Wang, Xiyang; Jensen, Peter E.; Chen, Xinjian

    2016-01-01

    Non-Hodgkin lymphoma (NHL) is one of the most common hematologic malignancies among adults for which the chimeric monoclonal anti-CD20 antibody (Ab) rituximab (RTX) is used as first-line therapy. As RTX itself is not directly cytotoxic but relies on host immune effector mechanisms or chemotherapeutic agents to attack target cells, its therapeutic capacity may become limited when host effector mechanisms are compromised. Currently, refractory disease and relapse with NHL are still common, highlighting the need for novel anti-CD20 antibody strategies with superior therapeutic efficacy over current protocols. We hypothesized that making RTX directly cytotoxic might improve the therapeutic efficacy. Graphene oxide (GO) has recently emerged as a highly attractive nanomaterial for biomedical applications; and several studies have reported cytotoxic effect of GO on benign and malignant cells in vitro. Herein, we report that RTX can be stably associated with GO, and that GO-associated RTX (RTX/GO) demonstrates remarkably high avidity for CD20. Binding of GO-associated RTX to CD20-positive lymphoma cells induces CD20 capping and target cell death through an actin dependent mechanism. In vivo, GO-associated RTX, but not free RTX, quickly eliminates high-grade lymphomas in the absence of host effector mechanisms in a xenograft lymphoma mouse model. Our findings represent the first demonstration of using GO-associated antibody as effective cytotoxic therapy for human B cell malignancies in the absence of chemotherapy, and these findings could have important clinical implications. PMID:26859679

  2. Intratumoral but not systemic delivery of CpG oligodeoxynucleotide augments the efficacy of anti-CD20 monoclonal antibody therapy against B cell lymphoma.

    PubMed

    Betting, David J; Yamada, Reiko E; Kafi, Kamran; Said, Jonathan; van Rooijen, Nico; Timmerman, John M

    2009-01-01

    The anti-CD20 monoclonal antibody rituximab (Rituxan) has become a mainstay in the treatment of B cell non-Hodgkin lymphomas. The mechanisms of action for rituximab include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and apoptosis induction. Combination of anti-CD20 antibodies with immunostimulatory agents may improve their efficacy via enhancement of one or more of these mechanisms. Toll-like receptor 9 agonist CpG oligodeoxynucleotides administered systemically have been studied in clinical trials with and without rituximab. However, recent data suggest that intratumoral (IT) delivery of CpG has advantages in the treatment of tumors. Using a syngeneic murine B cell lymphoma line expressing human CD20, we found that IT, but not systemically administered CpG significantly improved the efficacy of rituximab against 7-day established tumors. Rituximab plus IT CpG could eradicate tumors from 42% of mice, whereas systemically administered CpG, with or without rituximab, did not achieve tumor eradication. Both natural killer cells and complement participated in the cure of tumors by rituximab plus IT CpG, apparently by increasing tumor cell sensitivity to complement and ADCC lysis, and by augmenting the cytotoxicity of ADCC effectors. No role for T cells in mediating tumor eradication was demonstrated in this model. These results suggest that previous clinical trials in B cell lymphoma combining systemic administration of CpG with rituximab may have employed suboptimal routes of CpG delivery. Future trials combining IT CpG with anti-CD20 antibodies or the antibody-mediated targeting of CpG directly to the sites of B cell lymphoma may thus be warranted. PMID:19483647

  3. The Role of Monoclonal Antibodies in the Management of Leukemia

    PubMed Central

    Al-Ameri, Ali; Cherry, Mohamad; Al-Kali, Aref; Ferrajoli, Alessandra

    2010-01-01

    This article will review the monoclonal antibodies more commonly used in leukemias. In the last three decades, scientists have made considerable progress understanding the structure and the functions of various surface antigens, such as CD20, CD33. The introduction of rituximab, an anti CD20 monoclonal antibody, had a great impact in the treatment of lymphoproliferative disorders. Gemtuzumab, an anti CD 33 conjugated monoclonal antibody has activity in acute mylegenous leukemia (AML). As this field is undergoing a rapid growth, the years will see an increasing use of monoclonal antibodies in hematological malignancies.

  4. Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sjögren’s syndrome

    PubMed Central

    2014-01-01

    Introduction Subjects with primary Sjögren’s syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab. Methods To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period. Results Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection. Conclusions For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an

  5. Is rituximab an effective treatment of refractory calcinosis?

    PubMed

    Dubos, Maria; Ly, Kim; Martel, Clothilde; Fauchais, Anne Laure

    2016-01-01

    Calcinosis, the deposition of calcified material in soft tissues, is frequently seen in systemic sclerosis and dermatomyositis. Treatment options are limited, with disappointing results. Some recent case reports suggest that rituximab may be an attractive therapeutic option. In case 1, a 54-year-old woman who presented with rheumatoid arthritis in association with scleromyositis was treated with rituximab for rheumatoid arthritis. Despite this, she developed multiple progressive calcinosis, necessitating extracorporeal shock wave lithotripsy to limit calcinosis extension and pain. In case 2, a 38-year-old man, previously treated for an anti-Pm/Scl-positive polymyositis/scleroderma overlap syndrome, presented with multiple tumoural periarticular calcinosis, which progressed despite bisphosphonates, sodium thiosulfate and thalidomide. We decided to start rituximab. Progression of calcinosis was still evident 6 and 12 months after anti-CD20 treatment. Many treatments have been tried to treat calcinosis without demonstrated effectiveness. Presently, rituximab cannot be recommended for this indication in the absence of successful controlled trials. PMID:27247203

  6. Rituximab therapy for primary glomerulonephritis: Report on two cases

    PubMed Central

    Fabrizi, Fabrizio; Cresseri, Donata; Fogazzi, Giovanni B; Moroni, Gabriella; Passerini, Patrizia; Martin, Paul; Messa, Piergiorgio

    2015-01-01

    The evidence in the medical literature on the efficacy and safety of rituximab therapy for primary glomerulonephritis is limited and controversial. We describe two male Caucasian patients with rapidly progressive kidney failure due to primary proliferative glomerulonephritis. Both of them received high-dose intravenous corticosteroids and oral cyclophosphamide with limited benefit. The first patient (hepatitis C virus-negative mixed cryoglobulinemia) underwent plasma-exchange with intravenous immunoglobulins; he showed significant benefit on kidney function (he became dialysis independent with serum creatinine going back to 1.6 mg/dL) after one rituximab pulse even if urinary abnormalities were still present. No improvement in renal function or urinary changes occurred in the second patient. Both these individuals developed sepsis over the follow-up, the first patient died two months after rituximab therapy. This report is in keeping with the occurrence of severe infections after rituximab therapy in patients with renal impairment at baseline and concomitant high-dose steroids. PMID:26301235

  7. Tumor dosimetry in radioimmunotherapy: Methods of calculation for beta particles

    SciTech Connect

    Leichner, P.K. ); Kwok, C.S. )

    1993-03-01

    Calculational methods of beta-particle dosimetry in radioimmunotherapy (RIT) are reviewed for clinical and experimental studies and computer modeling of tumors. In clinical studies, absorbed-dose estimates are usually based on the [ital in]-[ital vivo] quantitation of the activity in tumors from gamma camera images. Because of the limited spatial resolution of gamma cameras, clinical dosimetry is necessarily limited to the macroscopic level (macrodosimetry) and the MIRD formalism for absorbed-dose calculations is appropriate. In experimental RIT, tumor dimensions are often comparable to or smaller than the beta-particle range of commonly used radionuclides (for example, [sup 131]I, [sup 67]Cu, [sup 186]Re, [sup 188]Re, [sup 90]Y) and deviations from the equilibrium dose must be taken into account in absorbed-dose calculations. Additionally, if small tumors are growing rapidly at the time of RIT, the effects of tumor growth will need to be included in absorbed-dose estimates. In computer modeling of absorbed-dose distributions, analytical, numerical, and Monte Carlo methods have been used to investigate the consequences of uniform and nonuniform activity distributions and the effects of inhomogeneous media. Measurements and calculations of the local absorbed dose at the multicellular level have shown that variations in this dose are large. Knowledge of the absorbed dose is essential for any form of radiotherapy. Therefore, it is important that clinical, experimental, and theoretical investigations continue to provide information on tumor dosimetry that is necessary for a better understanding of the radiobiological effects of RIT.

  8. Antibodies in the treatment of aplastic anemia.

    PubMed

    Gómez-Almaguer, David; Jaime-Pérez, Jose Carlos; Ruiz-Arguelles, Guillermo J

    2012-04-01

    Antibodies have been the cornerstone of treatment of acquired aplastic anemia for more than 25 years. Treatment with antithymocyte globulin (ATG) is considered pivotal and the addition of cyclosporine improves the overall response rate. This antibody is heterogeneous and horse ATG is apparently more effective than rabbit ATG. Several issues remain unsolved in relation to the combination of ATG and cyclosporine: cost, toxicity and late clonal disorders. In recent years, alternative immunosuppressive therapy has been proposed and new antibodies have emerged: porcine ATG, alemtuzumab, daclizumab, and rituximab. Experience with these antibodies is limited to a few studies with alemtuzumab being the most promising, but the results are interesting and provocative. More studies are needed to find the perfect antibody. PMID:22307362

  9. Time Savings with Rituximab Subcutaneous Injection versus Rituximab Intravenous Infusion: A Time and Motion Study in Eight Countries

    PubMed Central

    De Cock, Erwin; Kritikou, Persefoni; Sandoval, Mariana; Tao, Sunning; Wiesner, Christof; Carella, Angelo Michele; Ngoh, Charles; Waterboer, Tim

    2016-01-01

    Background Rituximab is a standard treatment for non-Hodgkin lymphoma. The SABRINA trial (NCT01200758) showed that a subcutaneous (SC) rituximab formulation did not compromise efficacy or safety compared with intravenous (IV) infusion. We aimed to quantify active healthcare professional (HCP) time and patient chair time for rituximab SC and IV, including potential time savings. Methods This non-interventional time and motion study was run in eight countries and 30 day oncology units. Rituximab SC data were collected alongside the MabCute trial (NCT01461928); IV data were collected per routine real-world practice. Trained observers recorded active HCP time for pre-specified tasks (stopwatch) and chair time (time of day). A random intercept model was used to analyze active HCP time (by task and for all tasks combined) in the treatment room and drug preparation area, drug administration duration, chair time and patient treatment room time by country and/or across countries. Active HCP and chair time were extrapolated to a patient’s first year of treatment (11 rituximab sessions). Results Mean active HCP time was 35.0 and 23.7 minutes for IV and SC process, respectively (-32%, p <0.0001). By country, relative reduction in time was 27–58%. Absolute reduction in extrapolated active HCP time (first year of treatment) was 1.1–5.2 hours. Mean chair time was 262.1 minutes for IV, including 180.9 minutes infusion duration, vs. 67.3 minutes for SC, including 8.3 minutes SC injection administration (-74%, p <0.0001). By country, relative reduction was 53–91%. Absolute reduction in extrapolated chair time for the first year of treatment was 3.1–5.5 eight-hour days. Conclusions Compared with rituximab IV, rituximab SC was associated with reduced chair time and active HCP time. The latter could be invested in other activities, whereas the former may lead to more available appointments, reducing waiting lists and increasing the efficiency of day oncology units. Trial

  10. [Monoclonal antibody for cancer treatment].

    PubMed

    Achiwa, Hiroyuki; Sato, Shigeki; Ueda, Ryuzo

    2002-04-01

    Antibodies have for many decades been viewed as ideal molecules for cancer therapy. Although promising from the start, it has taken much of more than two decades to reach the level of clinical application. Genetic engineering of antibodies; that is novel technologies for chimeric or humanizing monoclonal antibodies, has greatly advanced their utility in molecular targeting therapies, and in the past four years some therapeutic monoclonal antibodies for hematologic malignancies and solid tumors, such as Rituximab for B-cell lymphoma and Trastuzumab for metastatic breast cancer, have provided sufficient efficacy and safety to support regulatory approval from the U.S. Food and Drug Administration. They were subsequently approved by the Japanese Ministry of Health, Labour and Welfare in 2001. Many molecular biological and immunological studies have revealed the targeting properties of the host immune system and the biological mechanism of cancer cells for a more specific anticancer effect. Many clinical trials of monoclonal antibodies as a single agent, or in combination protocol with current standard chemotherapy or immunoconjugates have shown promise in the treatment of specific diseases. Furthermore, novel antibody designs and improved understanding of the mode of action of current antibodies lend great hope to the future of this therapeutic approach. The accumulating results from many basic, clinical and translational studies may lead to more individualized therapeutic strategies using these agent directed at specific genetic and immunologic targets. PMID:11977531

  11. Rituximab for the Treatment of Relapses in ANCA-associated Vasculitis

    PubMed Central

    Miloslavsky, EM; Specks, U; Merkel, PA; Seo, P; Spiera, R; Langford, CA; Hoffman, GS; Kallenberg, CGM; St. Clair, EW; Tchao, NK; Viviano, L; Ding, L; Ikle, D; Villarreal, M; Jepson, B; Brunetta, P; Allen, NB; Fervenza, FC; Geetha, D; Keogh, K; Kissin, EY; Monach, PA; Peikert, T; Stegeman, C; Ytterberg, SR; Stone, JH

    2014-01-01

    Introduction Disease relapses are frequent in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). We evaluated the outcomes of patients re-treated with rituximab (RTX) and prednisone for severe disease relapses. Methods The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After achieving remission, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a pre-specified protocol. Investigators remained blinded to the original treatment assignment. Results Twenty-six patients received treatment with RTX for disease relapse after initially achieving remission on their originally assigned treatment. Fifteen patients were initially randomized to RTX and 11 to CYC/AZA. Thirteen (87%) of the patients originally assigned to RTX and 10 (91%) originally assigned to CYC/AZA achieved remission again with open-label RTX, an overall percentage of 88%. Half of the patients treated with open-label RTX were able to discontinue prednisone entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events/patient-year versus 11.8 adverse events/patient-year, respectively). Conclusion Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment. PMID:25047592

  12. Cancer therapy with radiolabeled and drug/toxin-conjugated antibodies.

    PubMed

    Govindan, Serengulam V; Griffiths, Gary L; Hansen, Hans J; Horak, Ivan D; Goldenberg, David M

    2005-08-01

    Radioimmunotherapy and antibody-directed chemotherapy have emerged as cancer treatment modalities with the regulatory approval of products for non-Hodgkin's lymphoma and acute myeloid leukemia. Antibody-toxin therapy is likewise on the verge of clinical fruition. Accumulating evidence suggests that radioimmunotherapy may have the best impact in minimal-disease and adjuvant settings, especially with radioresistant solid tumors. For the latter, ongoing efforts in 'pretargeting' to increase deliverable tumor radiation dose, combination therapies, and locoregional applications are also of importance. Antibody-drug conjugates have the potential to increase the therapeutic index of chemotherapy by minimizing systemic toxicity and improving tumor targeting. The design of optimal drug conjugates in this regard is predicated upon the proper choice of the target antigen, the cleavable-linker, and the drug. In respect of antibody-toxin conjugates, considerable progress has been made in chemical and recombinant immunotoxin designs, and in the advancement of many products to clinical trials. Continued development of antibody-directed therapies should expand the options available for the management of cancer. PMID:16029057

  13. A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402.

    PubMed

    Witzig, Thomas E; Hong, Fangxin; Micallef, Ivana N; Gascoyne, Randy D; Dogan, Ahmet; Wagner, Henry; Kahl, Brad S; Advani, Ranjana H; Horning, Sandra J

    2015-09-01

    Patients with early stage diffuse large B-cell lymphoma (DLBCL) receive RCHOP (rituximab cyclophosphamide, doxorubicin, vincristine, prednisone) alone or with involved field radiotherapy (IFRT). Anti-CD20 radioimmunotherapy (RIT) delivers radiation to microscopic sites outside of known disease. This phase II study aimed to achieve a functional complete response (CR) rate of ≥75% to RCHOP and (90) Yttrium-ibritumomab tiuxetan RIT. Patients with stages I/II DLBCL received 4-6 cycles of RCHOP followed by RIT [14·8 MBq/kg (0·4 mCi/kg)]; patients with positron emission tomographypositive sites of disease after RCHOP/RIT received 30 Gy IFRT. Of the 62 patients enrolled; 53 were eligible. 42% (22/53) had stage I/IE; 58% (31/53) stage II/IIE. After RCHOP, 79% (42/53) were in CR/unconfirmed CR. Forty-eight patients proceeded to RIT. One partial responder after RIT received IFRT and achieved a CR. The best response after RCHOP + RIT in all 53 patients was a functional CR rate of 89% (47/53; 95% confidence interval: 77-96%). With a median follow-up of 5·9 years, 7 (13%) patients have progressed and 4 (8%) have died (2 with DLBCL). At 5 years, 78% of patients remain in remission and 94% are alive. Chemoimmunotherapy and RIT is an active regimen for early stage DLBCL patients. Eighty-nine percent of patients achieved functional CR without the requirement of IFRT. This regimen is worthy of further study for early stage DLBCL in a phase III trial. PMID:25974212

  14. A hybrid protein-polymer nanoworm potentiates apoptosis better than a monoclonal antibody.

    PubMed

    Aluri, Suhaas Rayudu; Shi, Pu; Gustafson, Joshua A; Wang, Wan; Lin, Yi-An; Cui, Honggang; Liu, Shuanglong; Conti, Peter S; Li, Zibo; Hu, Peisheng; Epstein, Alan L; MacKay, John Andrew

    2014-03-25

    B-cell lymphomas continue to occur with a high incidence. The chimeric antibody known as Rituximab (Rituxan) has become a vital therapy for these patients. Rituximab induces cell death via binding and clustering of the CD20 receptor by Fcγ expressing effector cells. Because of the limited mobility of effector cells, it may be advantageous to cluster CD20 directly using multivalent nanostructures. To explore this strategy, this manuscript introduces a nanoparticle that assembles from a fusion between a single chain antibody and a soluble protein polymer. These hybrid proteins express in Escherichia coli and do not require bioconjugation between the antibody and a substrate. Surprisingly a fusion between an anti-CD20 single chain antibody and a soluble protein polymer assemble worm-like nanostructures, which were characterized using light scattering and cryogenic transmission electron microscopy. These nanoworms competitively bind CD20 on two B-cell lymphoma cell lines, exhibit concentration-dependent induction of apoptosis, and induce apoptosis better than Rituximab alone. Similar activity was observed in vivo using a non-Hodgkin lymphoma xenograft model. In comparison to Rituximab, systemic nanoworms significantly slowed tumor growth. These findings suggest that hybrid nanoworms targeted at CD20 may be useful treatments for B-cell related malignancies. Because of the ubiquity of antibody therapeutics, related nanoworms may have uses against other molecular targets. PMID:24484356

  15. Anti-CD45 radioimmunotherapy using 211At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model

    PubMed Central

    Orozco, Johnnie J.; Bäck, Tom; Kenoyer, Aimee; Balkin, Ethan R.; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Frayo, Shani L.; Hylarides, Mark D.; Green, Damian J.; Gopal, Ajay K.; Press, Oliver W.

    2013-01-01

    Despite aggressive chemotherapy combined with hematopoietic stem cell transplantation (HSCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using monoclonal antibodies labeled with β-emitting radionuclides has been explored to reduce relapse. β emitters are limited by lower energies and nonspecific cytotoxicity from longer path lengths compared with α emitters such as 211At, which has a higher energy profile and shorter path length. We evaluated the efficacy and toxicity of anti-CD45 RIT using 211At in a disseminated murine AML model. Biodistribution studies in leukemic SJL/J mice showed excellent localization of 211At-anti-murine CD45 mAb (30F11) to marrow and spleen within 24 hours (18% and 79% injected dose per gram of tissue [ID/g], respectively), with lower kidney and lung uptake (8.4% and 14% ID/g, respectively). In syngeneic HSCT studies, 211At-B10-30F11 RIT improved the median survival of leukemic mice in a dose-dependent fashion (123, 101, 61, and 37 days given 24, 20, 12, and 0 µCi, respectively). This approach had minimal toxicity with nadir white blood cell counts >2.7 K/µL 2 weeks after HSCT and recovery by 4 weeks. These data suggest that 211At-anti-CD45 RIT in conjunction with HSCT may be a promising therapeutic option for AML. PMID:23471305

  16. Anti-CD45 radioimmunotherapy using (211)At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model.

    PubMed

    Orozco, Johnnie J; Bäck, Tom; Kenoyer, Aimee; Balkin, Ethan R; Hamlin, Donald K; Wilbur, D Scott; Fisher, Darrell R; Frayo, Shani L; Hylarides, Mark D; Green, Damian J; Gopal, Ajay K; Press, Oliver W; Pagel, John M

    2013-05-01

    Despite aggressive chemotherapy combined with hematopoietic stem cell transplantation (HSCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using monoclonal antibodies labeled with β-emitting radionuclides has been explored to reduce relapse. β emitters are limited by lower energies and nonspecific cytotoxicity from longer path lengths compared with α emitters such as (211)At, which has a higher energy profile and shorter path length. We evaluated the efficacy and toxicity of anti-CD45 RIT using (211)At in a disseminated murine AML model. Biodistribution studies in leukemic SJL/J mice showed excellent localization of (211)At-anti-murine CD45 mAb (30F11) to marrow and spleen within 24 hours (18% and 79% injected dose per gram of tissue [ID/g], respectively), with lower kidney and lung uptake (8.4% and 14% ID/g, respectively). In syngeneic HSCT studies, (211)At-B10-30F11 RIT improved the median survival of leukemic mice in a dose-dependent fashion (123, 101, 61, and 37 days given 24, 20, 12, and 0 µCi, respectively). This approach had minimal toxicity with nadir white blood cell counts >2.7 K/µL 2 weeks after HSCT and recovery by 4 weeks. These data suggest that (211)At-anti-CD45 RIT in conjunction with HSCT may be a promising therapeutic option for AML. PMID:23471305

  17. Clinical efficacy of combined rituximab treatment in a woman with severe Graves' ophthalmopathy

    PubMed Central

    Liu, Xiaomei; Guo, Hui; Liu, Juan; Shi, Bingyin

    2016-01-01

    The present study reports the case of a female Chinese patient with Graves' disease (GD) and severe Graves' ophthalmopathy (GO) in its active phase, who was treated with propylthiouracil and oral prednisolone for 2 months at a local hospital. However, a lack of improvement in symptoms meant that the patient was transferred to the First Affiliated Hospital of Xi'an Jiaotong University (Xi'an, China), whereupon the patient received high-dose intravenous methylprednisolone pulse therapy, although with limited efficacy. Subsequently, rituximab (RTX; anti-CD20 monoclonal antibody) combined with orbital irradiation treatment was initiated. The patient responded positively to the combined treatment; the clinical symptoms and enlargement of the extraocular muscles were ameliorated, and there were marked decreases in the clinical activity and NOSPECS grading scores. Furthermore, the serum levels of anti-thyrotropin receptor antibodies (TRAb) were markedly decreased at 2 months following RTX therapy. The patient was maintained in a euthyroid state by treatment with methimazole during and following RTX therapy. It was concluded that RTX treatment may attenuate severe GO by depleting lymphocytes, and may promote the recovery of GD by reducing the serum levels of TRAb. PMID:27446325

  18. Monoclonal antibodies in the treatment of cancer

    SciTech Connect

    Dillman, R.O.

    1984-01-01

    Potential uses of monoclonal antibodies in anti-cancer treatment include passive serotherapy, radioisotope conjugates, toxin-linked conjugates, and chemotherapy-monoclonal antibody conjugates. The bases for these applications have been founded in research with heterologous antisera, and in some cases with monoclonal antibodies in animal tumor models. Human trials with passive serotherapy have already begun in both hematopoietic and solid tumor malignancies. Promising results have been reported in cutaneous T cell lymphoma with anti-T cell monoclonal antibody, and in nodular lymphoma with anti-idiotype monoclonal antibody. Radioisotope conjugate work appears promising for imaging in both animals and humans, and this work will lay the foundation for possible therapeutic application of radio-immunotherapy. Toxin-linked conjugates are promising in vitro and may have application in autologous bone marrow transplantation. Research with chemotherapy conjugates is also underway. Preliminary results suggest that murine monoclonal antibodies will be well tolerated clinically except in the setting of circulating cells which bear the target antigen, where rapid infusions may be associated with intolerable side effects. In certain diseases, production of endogenous anti-mouse antibodies may also limit application. Advances in the technology for human-human hybridoma production may help solve some of these problems. 132 references.

  19. Engineering antibodies for clinical applications in cancer.

    PubMed

    Chester, Kerry; Pedley, Barbara; Tolner, Berend; Violet, John; Mayer, Astrid; Sharma, Surinder; Boxer, Geoff; Green, Alan; Nagl, Sylvia; Begent, Richard

    2004-01-01

    The 'magic bullet' concept predicted over a century ago that antibodies would be used to target cancer therapy. Since then initial problems that were related to specificity, purity and immungenicity of antibody-based reagents have slowly been overcome due to developments in technology and increased knowledge. As a result, antibodies are in use for many clinical applications and now comprise the second largest category of medicines in clinical development after vaccines. For antibody-based cancer therapeutics the last 20 years have met with an explosion of knowledge about the biology of the disease and potential targets as well as new technology which allows cloning and manipulation of multifunctional antibody-based molecules. However, the focus still remains on developing therapeutics that will have potential for treating cancer in people and this is efficiently assessed in mechanistic clinical trials that feed back to the laboratory for further development. This review illustrates the mechanistic approach to making new molecules for antibody imaging and therapy of cancer. It is illustrated by examples of radioimmunotherapy and antibody-directed enzyme prodrug therapy developed by the authors. PMID:15192316

  20. Protein biochip array technology to monitor rituximab in rheumatoid arthritis

    PubMed Central

    Fabre, S; Guisset, C; Tatem, L; Dossat, N; Dupuy, A M; Cohen, J D; Cristol, J P; Daures, J P; Jorgensen, C

    2009-01-01

    In rheumatoid arthritis (RA) there are currently no good indicators to predict a clinical response to rituximab. The purpose of this study was to monitor and determine the role of peripheral blood cytokine profiling in differentiating between a good versus poor response to rituximab in RA. Blood samples were collected at baseline and at 3 months from 46 RA patients who were treated with rituximab. Responders are defined by the presence of three of four American College of Rheumatology criteria: ≥ 20% decrease in C-reactive protein, visual analogical score of disease activity, erythrocyte sedimentation rate and improvement of the disease activity score (28) (four values) by ≥ 1·2 obtained at 3 months. Twelve cytokines were measured from serum collected on days 0 and 90 by proteomic array, including interleukin-6 (IL-6), tumour necrosis factor-α, IL-1a, IL-1b, IL-2, IL-8, interferon-γ, IL-4, IL-10, monocyte chemoattractant protein-1, epidermal growth factor and vascular growth factor. We showed that C-reactive protein and IL-6 levels decrease significantly at 3 months in the responder group compared with baseline. At day 90 we identified a cytokine profile which differentiates responders and non-responders. High serum levels of two proinflammatory cytokines, monocyte chemoattractant protein-1 and epidermal growth factor, were significantly higher in the responder group at day 90 compared with non-responders. However, we were not able to identify a baseline cytokine profile predictive of a good response at 3 months. These findings suggest that cytokine profiling by proteomic analysis may be a promising tool for monitoring rituximab and may help in the future to identify responder RA patients. PMID:19220830

  1. Combined therapy with rituximab plus cyclophosphamide/vincristine/prednisone for Sjogren's syndrome-associated B-cell non-Hodgkin's lymphoma.

    PubMed

    Carbone, J; Perez-Fernandez, R; Muñoz, A; Sabin, P; Carreño, L; Fernandez-Cruz, E

    2008-02-01

    Sjogren's syndrome (SS) is characterized by an increased risk of developing non-Hodgkin's lymphoma (NHL). Optimal treatment for NHL-complicating SS is not clearly established. NHL, which expresses the CD20 antigen on tumor cell surfaces, is a disease entity candidate to treatment with anti-CD20 monoclonal antibodies. We report clinical and immunological data of a patient with SS and NHL who was treated with a regimen consisting of cyclophosphamide/vincristine/prednisone (CVP) plus rituximab. A 68-year-old women had a 26-year history of SS and autoimmune thyroiditis. The clinical course of SS was complicated with severe splenomegaly. An increased percentage of CD19+ B cells (up to 30%) was detected in peripheral blood during follow-up. Clonal rearrangement of immunoglobulin heavy chain was detected. Low-grade B marginal zone lymphoma was diagnosed (peripheral blood immunophenotype: CD19+CD20+CD23+sIg+Kappa; bone marrow immunophenotype: 25% lymphocytes; CD19+CD20+CD79A/BCL2+). She received a total of six cycles of CVP plus rituximab (375 mg/m2). Therapy was well tolerated, and B lymphocytes were depleted from the peripheral blood. Splenomegaly normalized. No evidence of neoplastic infiltration was detected in bone marrow after completion of therapy, while certain symptoms of SS (sicca and arthralgia) improved with treatment. CVP plus rituximab proved effective in a patient with SS with NHL. PMID:18270861

  2. Rituximab does not reset defective early B cell tolerance checkpoints

    PubMed Central

    Chamberlain, Nicolas; Massad, Christopher; Oe, Tyler; Cantaert, Tineke; Herold, Kevan C.; Meffre, Eric

    2015-01-01

    Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve β cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti–B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti–B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti–B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti–B cell therapy. PMID:26642366

  3. [Successful treatment with rituximab and romiplostim for thrombocytopenia associated with Waldenström's macroglobulinemia initially presenting as Evans syndrome].

    PubMed

    Nozaki, Yumi; Koshiishi, Megumi; Sueki, Yuki; Kawashima, Ichirou; Yamamoto, Takeo; Nakajima, Kei; Mitsumori, Toru; Kirito, Keita

    2015-03-01

    A 60-year-old woman was admitted to our hospital with anemia and thrombocytopenia. Serum testing showed platelet-associated IgG elevation and she was positive on the direct and indirect Coombs tests. Together with bone marrow examination, these findings indicated a diagnosis of Evans syndrome. At diagnosis, she also had an IgM-κ type of monoclonal gammopathy of unknown significance. Initially, we administered steroids and her hemolytic anemia showed improvement. In contrast, only transient recovery of platelet counts was observed and her platelet counts rapidly decreased after steroid dose reduction. Thus, we treated her with a TPO-agonist, romiplostim. During the clinical course, she showed gradual serum IgM elevation. We thus performed another bone marrow biopsy and diagnosed her as having Waldenström's macroglobulinemia (WM). We started treatment with rituximab for WM. Together with the serum IgM reduction, she showed marked improvement of thrombocytopenia. This is a very rare case of WM initially presenting as autoimmune hemolytic anemia and immunethrombocytopenia associated with IgG class auto-antibody. Our experience suggests the usefulness of rituximab and romiplostim for the treatment of immunethrombocytopenia associated with WM. PMID:25876786

  4. Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients

    PubMed Central

    Levi, Marilyn E.; Quan, Dianna; Ho, Joseph T.; Kleinschmidt-DeMasters, B. K.; Tyler, Kenneth L.; Grazia, Todd J.

    2010-01-01

    Evidence suggests that West Nile virus (WNV) neuroinvasive disease occurs more frequently in both solid organ and human stem cell transplant recipients. The effect of concomitant anti-B-cell therapy with rituximab, a CD20+ monoclonal antibody, on WNV infection in this population, however, has not been reported. We describe a case of a patient with alpha-1-antitrypsin deficiency who underwent single lung transplantation in 2005 and was maintained on tacrolimus, cytoxan and prednisone. More recently, she had received two courses of rituximab for recurrent A2–A3 grade rejection with concomitant capillaritis and presented six months later with rapid, fulminant WNV meningoencephalitis. Her diagnosis was made by cerebrospinal fluid (CSF) PCR but serum and CSF WNV IgM and IgG remained negative. She received WNV-specific hyperimmune globulin (Omr-Ig-Am®) through a compassionate protocol. She experienced a rapidly progressive and devastating neurological course despite treatment and died three wk after onset of her symptoms. Autopsy revealed extensive meningoencephalomyelitis. PMID:19659514

  5. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

    PubMed Central

    Walewski, Jan; Döhner, Hartmut; Viardot, Andreas; Hiddemann, Wolfgang; Spiekermann, Karsten; Serve, Hubert; Dührsen, Ulrich; Hüttmann, Andreas; Thiel, Eckhard; Dengler, Jolanta; Kneba, Michael; Schaich, Markus; Schmidt-Wolf, Ingo G. H.; Beck, Joachim; Hertenstein, Bernd; Reichle, Albrecht; Domanska-Czyz, Katarzyna; Fietkau, Rainer; Horst, Heinz-August; Rieder, Harald; Schwartz, Stefan; Burmeister, Thomas; Gökbuget, Nicola

    2014-01-01

    This largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P = .0005), age-adjusted IPI score (0-1 vs 2-3; P = .0001), and gender (male vs female; P = .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082. PMID:25359988

  6. Recent developments in monoclonal antibody radiolabeling techniques

    SciTech Connect

    Srivastava, S.C.; Mease, R.C.

    1989-01-01

    Monoclonal antibodies (MAbs) have shown the potential to serve as selective carriers of radionuclides to specific in vivo antigens. Accordingly, there has been an intense surge of research activity in an effort to develop and evaluate MAb-based radiopharmaceuticals for tumor imaging (radioimmunoscintigraphy) and therapy (radioimmunotherapy), as well as for diagnosing nonmalignant diseases. A number of problems have recently been identified, related to the MAbs themselves and to radiolabeling techniques, that comprise both the selectivity and the specificity of the in vivo distribution of radiolabeled MAbs. This paper will address some of these issues and primarily discuss recent developments in the techniques for radiolabeling monoclonal antibodies that may help resolve problems related to the poor in vivo stability of the radiolabel and may thus produce improved biodistribution. Even though many issues are identical with therapeutic radionuclides, the discussion will focus mainly on radioimmunoscintigraphic labels. 78 refs., 6 tabs.

  7. Radioimmunotherapy of breast cancer metastases with alpha-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y.

    PubMed

    Song, Hong; Hobbs, Robert F; Vajravelu, Ravy; Huso, David L; Esaias, Caroline; Apostolidis, Christos; Morgenstern, Alfred; Sgouros, George

    2009-12-01

    alpha-Particles are suitable to treat cancer micrometastases because of their short range and very high linear energy transfer. alpha-Particle emitter (213)Bi-based radioimmunotherapy has shown efficacy in a variety of metastatic animal cancer models, such as breast, ovarian, and prostate cancers. Its clinical implementation, however, is challenging due to the limited supply of (225)Ac, high technical requirement to prepare radioimmunoconjugate with very short half-life (T(1/2) = 45.6 min) on site, and prohibitive cost. In this study, we investigated the efficacy of the alpha-particle emitter (225)Ac, parent of (213)Bi, in a mouse model of breast cancer metastases. A single administration of (225)Ac (400 nCi)-labeled anti-rat HER-2/neu monoclonal antibody (7.16.4) completely eradicated breast cancer lung micrometastases in approximately 67% of HER-2/neu transgenic mice and led to long-term survival of these mice for up to 1 year. Treatment with (225)Ac-7.16.4 is significantly more effective than (213)Bi-7.16.4 (120 microCi; median survival, 61 days; P = 0.001) and (90)Y-7.16.4 (120 microCi; median survival, 50 days; P < 0.001) as well as untreated control (median survival, 41 days; P < 0.0001). Dosimetric analysis showed that (225)Ac-treated metastases received a total dose of 9.6 Gy, significantly higher than 2.0 Gy from (213)Bi and 2.4 Gy from (90)Y. Biodistribution studies revealed that (225)Ac daughters, (221)Fr and (213)Bi, accumulated in kidneys and probably contributed to the long-term renal toxicity observed in surviving mice. These data suggest (225)Ac-labeled anti-HER-2/neu monoclonal antibody could significantly prolong survival in HER-2/neu-positive metastatic breast cancer patients. PMID:19920193

  8. The clinical application of monoclonal antibodies in chronic lymphocytic leukemia

    PubMed Central

    Jaglowski, Samantha M.; Alinari, Lapo; Lapalombella, Rosa; Muthusamy, Natarajan

    2010-01-01

    Chronic lymphocytic leukemia (CLL) represents the most prevalent adult leukemia. Treatment with chemotherapy over the past 3 decades has been palliative. The introduction of therapeutic antibodies has increased the number of treatment options for this disease. Despite this increase, our true understanding of the mechanism of action of antibody therapy in CLL remains limited. Rituximab, a CD20 antibody, is currently widely used in combination-based strategies for both previously untreated symptomatic CLL and as salvage therapy. Recent data suggest that the addition of rituximab to fludarabine with or without cyclophosphamide prolongs survival in younger patients with CLL. Other improved CD20 antibodies with promising clinical activity, including ofatumumab and GA-101, are coming forward. Alemtuzumab, a CD52 antibody, likewise has demonstrated benefit in both symptomatic, previously untreated CLL and in patients with relapsed disease but has less selectivity. Development of other therapeutic antibodies targeting alternative B-cell–specific antigens in CLL has been less successful, although many promising candidate antibodies and/or small modular immune pharmaceuticals (SMIPs) are coming forward. In addition, recent efforts to combine currently applied therapeutic antibodies with other biologic and targeted therapies with efficacy in CLL offers the potential to move toward alternative non–chemotherapy-based treatment approaches. PMID:20610811

  9. Radiolabeled monoclonal antibodies for imaging and therapy: Potential, problems, and prospects: Scientific highlights

    SciTech Connect

    Srivastava, S.C.; Buraggi, G.L.

    1986-01-01

    This meeting focused on areas of research on radiolabeled monoclonal antibodies. Topics covered included the production, purification, and fragmentation of monoclonal antibodies and immunochemistry of hybridomas; the production and the chemistry of radionuclides; the radiohalogenation and radiometal labeling techniques; the in-vivo pharmacokinetics of radiolabeled antibodies; the considerations of immunoreactivity of radiolabeled preparations; the instrumentation and imaging techniques as applied to radioimmunodetection; the radiation dosimetry in diagnostic and therapeutic use of labeled antibodies; the radioimmunoscintigraphy and radioimmunotherapy studies; and perspectives and directions for future research. Tutorial as well as scientific lectures describing the latest research data on the above topics were presented. Three workshop panels were convened on ''Methods for Determining Immunoreactivity of Radiolabeled Monoclonal Antibodies - Problems and Pitfalls,'' Radiobiological and Dosimetric Considerations for Immunotherapy with Labeled Antibodies,'' and ''The Human Anti-Mouse Antibody Response in Patients.''

  10. Cancer radioimmunotherapy: Development of an effective approach. Progress report, 1985

    SciTech Connect

    DeNardo, S.J.

    1985-12-31

    The objective of this program is the development of effective approaches for delivering radiation therapy to patients with cancer using radiopharmaceuticals produced from monoclonal antibodies. One major achievement of this program has been the development of a new, Cu-67 chelator (Teta). This chelator firmly holds copper even in the presence of competitive serum proteins. Copper has proven to be labile with other chelators. Also, a single photon emission tomographic camera was purchased with University and philanthropic funds specifically for this program. This allows full-time developmental work on quantitative imaging approaches and in vivo kinetics of our various radiopharmaceutical antibody products. The pharmakinetics of I-123 antibody and antibody fragments have been obtained in patients utilizing quantitative imaging and have demonstrated significant differences as well as the need for long- term studies with I-131 and Cu-67.

  11. Improved radioimmunotherapy of hematologic malignancies. Progress report, 1988--1991

    SciTech Connect

    Press, O.W.; Barofsky, D.F.

    1991-12-31

    This progress report describes accomplishments under four headings, namely: The study of the relative rates of metabolic degradation of radiolabeled monoclonal antibodies (MAb) targeting tumor associated antigens; Effects of lysosomotropic amines, carboxylic ionophores, and thioamides on the retention of radiolabeled MAbs by tumor cells; Subcellular site of radioimmunoconjugate degradation and the sizes of fragments generated by intracellular metabolism of radiolabeled antibodies; and Patterns of metabolic degradation of radioimmunoconjugates made with different techniques and with different radionuclides.

  12. Biosimilar monoclonal antibodies in lymphoma: a critical appraisal.

    PubMed

    Rioufol, Catherine; Salles, Gilles

    2015-05-01

    Rituximab, an anti-CD20 monoclonal antibody, revolutionized the treatment of lymphoma. Although newer generation anti-CD20 monoclonal antibodies are being examined, patent expiries and patient demand have fueled the development of rituximab biosimilars. The development of such agents is both an important and difficult undertaking. By definition, although they aim to have safety and efficacy comparable with their reference agents, biosimilars are not exact replicas of those agents, and small changes in nonclinical and preclinical properties may ultimately affect in vivo activity. Consideration must be given to the complex mechanisms of action, sensitive patient populations that may be treated, and appropriate clinical trial endpoints. Furthermore, extrapolation of indications is multifaceted, deserving close examination. This review represents a critical look at biosimilars in lymphoma and their safety, efficacy and long-term effects on patient outcomes. PMID:25818308

  13. Effectiveness of Rituximab in Severe Wegener’s Granulomatosis: Report of Two Cases and Review of the Literature

    PubMed Central

    Oristrell, Joaquim; Bejarano, Guillermina; Jordana, Rosa; Monteagudo, Manuel; Marí, Begoña; Casanovas, Arnau; Tolosa, Carles

    2009-01-01

    We hereby describe the satisfactory evolution of rituximab treatment in two patients with Wegener’s granulomatosis (WG). Rituximab was indicated for refractoriness to standard treatment in one case and life-threatening myelotoxicity due to alkylating agents in the other. A brief review of previous experience with the use of rituximab in the treatment of WG is presented. PMID:19590594

  14. Rituximab in the treatment of shrinking lung syndrome in systemic lupus erythematosus.

    PubMed

    Peñacoba Toribio, Patricia; Córica Albani, María Emilia; Mayos Pérez, Mercedes; Rodríguez de la Serna, Arturo

    2014-01-01

    Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus. We report the case of a patient with non-responding SLS (neither to glucocorticoids nor immunosupresors), who showed remarkable improvement after the onset of treatment with rituximab. Although there is a little evidence, treatment with rituximab could be proposed in SLS when classical treatment fails. PMID:24315464

  15. Efficiency of treatment with rituximab in platelet transfusion refractoriness: a study of 7 cases

    PubMed Central

    Liu, Wenbin; Wu, Dijiong; Hu, Tonglin; Ye, Baodong

    2015-01-01

    Objective: The purpose of our study was to evaluate the efficacy and safety of rituximab in treatment of immune PR. Methods: We retrospective analysis 7 paitents (5 aplastic anemia, 2 myelodysplastic syndrome) with immune PR who received at least 3 weekly infusions of rituximab (375 mg/m2). Results: All enrolled patients acquired improvement of platelets transfusion more than 2 months (CCI ≥ 4.5 × 109/L). We first found that there were 2 patterns of response to rituximab treatment in patients with immune PR, which the early but transient after the first rituximab administration and the late but continuous beginning to appear at 3 weeks from the start of treatment. Conclusion: Rituximab is a promising treatment in patients with immune PR and giving the opportunity and time for cure the disease. PMID:26550372

  16. Improving the treatment outcome of patients with chronic lymphocytic leukemia through targeted antibody therapy.

    PubMed

    Stephens, Deborah M; Byrd, John C

    2013-04-01

    Therapy for chronic lymphocytic leukemia (CLL) has evolved dramatically throughout the years. In 1997, rituximab (Rituxan), a CD20 monoclonal antibody (mAb), became the first mAb approved by the Food and Drug Administration for marketing in the treatment of cancer, specifically targeting B-cell malignancies. Over the last 10 years, rituximab or other mAbs including alemtuzumab and ofatumumab have become an integral part of the standard of care for CLL patients as single agents or in combination with chemotherapy or other immunotherapy. This review discusses the currently approved and novel mAbs for the treatment of CLL. PMID:23561475

  17. [Rituximab (MabThera)--a new biological medicine in rheumatoid arthritis therapy].

    PubMed

    Nemec, P

    2007-11-01

    Rheumatoid arthritis (RA) is a serious, chronic, inflammatory disorder that damages the joints. The chronic destructive process causes pain to patients with RA and leads to the development of permanent disability. At present, great emphasis is placed on timely and effective therapy for RA, which is able to halt or slow the development of the disorder. At present we do not have any means of curing RA, the main objective for treatment is to induce remission of the disorder and prevent structural damage to the joints and the development of permanent disability. The relatively frequent failure of disease modifying medications (DMARDs) lead to efforts to find new resources for the treatment of RA. So called biological medicines were recently introduced into therapeutic use. These were mainly TNFalpha blockers. Experience has shown that approximately a third of patients with RA do not respond even to treatment with such medicines. Rituximab (MabThera), a monoclonal antibody against CD20 positive B-lymphocytes, is a new biological medicine approved for RA therapy. It represents a new hope for patients with active RA, for whom earlier therapy with TNFa blockers has failed. PMID:18277630

  18. An Efficient Bifunctional Decadentate Ligand 3p-C-DEPA for Targeted Alpha Radioimmunotherapy Applications

    PubMed Central

    Song, Hyun A; Kang, Chi Soo; Baidoo, Kwamena E.; Milenic, Diane E.; Chen, Yunwei; Dai, Anzhi; Brechbiel, M. W.; Chong, Hyun-Soon

    2011-01-01

    A new bifunctional ligand 3p-C-DEPA was synthesized and evaluated for use in targeted alpha radioimmunotherapy. 3p-C-DEPA was efficiently prepared via regiospecific ring opening of an aziridinium ion and conjugated with trastuzumab. The 3p-C-DEPA-trastuzumab conjugate was extremely rapid in binding 205/6Bi, and the corresponding 205/6Bi-3p-C-DEPA-trastuzumab complex was stable in human serum. Biodistribution studies were performed to evaluate in vivo stability and tumor targeting of 205/6Bi-3p-C-DEPA-trastuzumab conjugate in tumor bearing athymic mice. 205/6Bi-3p-C-DEPA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low organ uptake and high tumor uptake. The results of the in vitro and in vivo studies indicate that 3p-C-DEPA is a promising chelator for radioimmunotherapy of 212Bi and 213Bi. PMID:21604692

  19. Treatment of Rheumatoid Arthritis with Biologic DMARDS (Rituximab and Etanercept)

    PubMed Central

    Gashi, Afrim A.; Rexhepi, Sylejman; Berisha, Idriz; Kryeziu, Avni; Ismaili, Jehona; Krasniqi, Gezim

    2014-01-01

    ABSTRACT Goal: To determine efficacy and safety of treatment with Rituximab and Etanercept plus Methotrexate in patients with active Rheumatoid Arthritis (RA), who had an inadequate response to nonbiologic DMARDS therapies and to explore the pharmacogenetics and pharmacodynamics of Rituximab and Etanercept in our populations. Study was done at Rheumatology Clinic of University Clinical Centre in Prishtina during 2009-2011 years. Methods: We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the study of long term efficacy of Rituximab and Etanercept. Patients with active Rheumatoid Arthritis and an inadequate response to 1 or more non biologic DMARDS were randomized to receive intravenous Rituximab (1 course consisting of 2 infusions of 1.000 mg each –one group, and Etanercept 25 mg twice weekly –second group, but both groups with background MTX. The primary efficacy end point was a response on the ACR 20%, improvement criteria at 24 weeks, Secondary end points were responses on the ACR 50 and ACR 70, improvement criteria, the DAS 28, and EULAR response criteria at 24 weeks. Results: During our investigations we treated 20 patients, 15 females and 5 males, in the treated group with RTX and 13 patients 8 females and 5 males in the treated group with ETN. Patients of group 1 and group 2 were of ages 37-69 years old and 19-69 years old (average 47-44) Most of the patients belong in 2nd and 3 rd functional stage according to Steinbrocker. All ACR response parameters were significantly improved in RTX treated patients who also had clinically meaningful improvement in fatigue, disability and quality of life. Patients showed a trend less progression in radiographic end points. Most adverse events occurred with the first RTX infusion and were mild to moderate severity. Conclusion: At 24 weeks, a single course of RTX and ETN provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who

  20. SpeB proteolysis with imaged capillary isoelectric focusing for the characterization of domain-specific charge heterogeneities of reference and biosimilar Rituximab.

    PubMed

    Zhang, Zichuan; Perrault, Ronel; Zhao, Yun; Ding, Julia

    2016-05-01

    The charge variations of therapeutic monoclonal antibody reveal important information of the post-translational modifications that may potentially impact the potency and safety of pharmaceutical products, especially during the evaluation of biosimilarity of therapeutic proteins. In this work, a novel SpeB-based proteolysis strategy coupling with imaged capillary isoelectric focusing was developed for the determination of domain-specific charge heterogeneities of innovator and generic Rituximab drug products from United States, European and Indian markets. It was observed that innovator Rituximab from the United States and Europe share highly similar peak distributions and charge heterogeneities with 26.2-26.6% Fc/2, 28.9-29.3% LC and 44.4-44.5% Fd peak areas detected, respectively, while multiple basic variations of Fc/2 and less acidic LC and Fd species were found from generic Rituximab from India with 20.9% Fc/2, 32.3% LC and 46.9% Fd peak areas detected. It was also demonstrated that structural changes caused by Carboxypeptidase B treatment and deamidation study at pH extremes could be sensitively captured with the established method, with the results further indicating that the generic product's basic variations of Fc/2 were un-cleaved Lysine residues, while the lack of certain acidic peaks on LC and Fd probably was due to the lower level of deamidation. This new strategy could become a useful tool to reveal domain-specific charge heterogeneities profiles of a variety of therapeutic monoclonal antibodies in regulated environments. PMID:27038651

  1. A Study of Rituximab and Ifosfamide, Carboplatin, and Etoposide Chemotherapy in Children with Recurrent/Refractory B-cell (CD20+) Non-Hodgkin Lymphoma and Mature B-Cell Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group

    PubMed Central

    Griffin, Timothy C.; Weitzman, Sheila; Weinstein, Howard; Chang, Myron; Cairo, Mitchell; Hutchison, Robert; Shiramizu, Bruce; Wiley, Joseph; Woods, Deborah; Barnich, Margaret; Gross, Thomas G.

    2009-01-01

    Background To estimate the response rate and therapy related toxicities of the anti-CD20 monoclonal antibody rituximab when combined with chemotherapy including ifosfamide, carboplatin, and etoposide (ICE) in patients with relapsed and refractory B-cell non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia (B-ALL). Methods Patients received rituximab and ICE for 1 to 3 cycles, depending upon response. Rituximab (375 mg/m2) was given on day 1 and 3 of each cycle (day 1 only for cycle 3), with ifosfamide (3000 mg/m2) and etoposide (100 mg/m2) given on days 3, 4, and 5 and carboplatin (635 mg/m2) given on day 3 only. Results Twenty-one patients were enrolled, of whom 20 were eligible and evaluable. Although hematologic toxicities were common, only one patient was removed from study due to prolonged myelosuppression. Toxicities related to infusions of rituximab were frequent but manageable. Of the 6 eligible patients with diffuse large B-cell lymphoma, 3 achieved complete remission (CR), 1 had stable disease (SD), and 2 had progressive disease (PD). Of the 14 eligible patients with Burkitt lymphoma and B-ALL, there were 4 complete responses (CR), 5 partial responses (PR), 1 SD and 4 with PD. Thus the CR/PR rate for the entire group was 12/20 (60%). Following completion of protocol therapy 6 patients were able to proceed to consolidation with high-dose therapy and stem cell rescue. Conclusions The combination of rituximab and ICE chemotherapy was associated with an encouraging objective response rate and an acceptable toxicity profile. PMID:18816698

  2. Current status of antibody therapy in ALL.

    PubMed

    Ai, Jing; Advani, Anjali

    2015-02-01

    Despite the significant advances in modern chemotherapy, it remains challenging to treat adult patients with acute lymphoblastic leukaemia (ALL). The relapse rate remains high, and the outcome at the time of relapse is dismal. Antibody-based therapies have demonstrated promising results in this patient group. Variable mechanisms have been applied to target surface antigens (CD20 [also termed MS4A1], CD22, CD52 and CD19) that are commonly expressed on malignant leukaemia cells. In this review, we will focus on the clinical application of such therapies in adult ALL, including the naked antibodies: Rituximab, Ofatumumab, Epratuzumab and Alemtuzumab; the immunotoxins: BL22 and Combotox; the immunoconjugates: inotuzumab and SAR 3419; as well as the Bi-specific T cell engaging (BiTE)-specific antibody, Blinatumomab. PMID:25382151

  3. High resolution computed tomography and MRI for monitoring lung tumor growth in mice undergoing radioimmunotherapy: correlation with histology.

    PubMed

    Kennel, S J; Davis, I A; Branning, J; Pan, H; Kabalka, G W; Paulus, M J

    2000-05-01

    A model lung tumor system has been developed in mice for the evaluation of vascular targeted radioimmunotherapy. In this model, EMT-6 mammary carcinoma tumors growing in the lung are treated with 213Bi, an alpha particle emitter, which is targeted to lung blood vessels using a monoclonal antibody. Smaller tumors (< 100 microm in diameter) are cured, but larger tumors undergo a period of regression and then regrow and ultimately prove lethal. The goal of this work was to determine if external imaging with MRI or CT could be used routinely to monitor the growth/ regression of lung tumors in live mice. To attempt to evaluate individual tumors in vivo, animals were initially imaged with magnetic resonance imaging (MRI). High resolution MRI images could be obtained only after sacrifice when lungs were not moving. In contrast, high resolution computed tomography (CT) produced evaluable images from anesthetized animals. Serial CT images (up to 5/animal) were collected over a 17 day period of tumor growth and treatment. When tumored animals became moribund, animals were sacrificed and lungs were inflated with fixative, embedded in paraffin, and then sectioned serially to compare the detection of tumors by high resolution CT with detection by histology. CT proved most useful in detecting lung tumors located in the hilar area and least useful in detecting serosal surface and anterior lobe tumor foci. Overall, CT images of live animals revealed tumors in approximately 2/3 of cases detected in histologic serial sections when relatively few tumors were present per lung. Detection of lesions and their resolution post therapy were complicated due to residual hemorrhagic, regressing tumor nodules and the development of lung edema both of which appeared as high density areas in the CT scans. We conclude that the microCT method used could identify some lung tumors as small as 100 microm in diameter; however, no concrete evaluation of therapy induced regression of the tumors could be

  4. 131I-tositumomab myeloablative radioimmunotherapy for non-Hodgkin’s lymphoma: radiation dose to the testes

    SciTech Connect

    Hattori, Naoya; Gopal, Ajay K.; Shields, Andrew T.; Fisher, Darrell R.; Gooley, Ted; Pagel, John M.; Press, Oliver W.; Rajendran, Joseph G.

    2012-12-01

    Purpose: To investigate radiation doses to the testes delivered by a radiolabeled anti-CD20 antibody and its effects on male sex hormone levels. Materials and methods: Testicular uptake and retention of 131I-tositumomab were measured, and testicular absorbed doses were calculated for 67 male patients (54+/-11 years of age) with non-Hodgkin's lymphoma who had undergone myeloablative radioimmunotherapy (RIT) using 131I-tositumomab. Time-activity curves for the major organs, testes, and whole body were generated from planar imaging studies. In a subset of patients, male sex hormones were measured before and 1 year after the therapy. Results: The absorbed dose to the testes showed considerable variability (range=4.4-70.2 Gy). Pretherapy levels of total testosterone were below the lower limit of the reference range, and post-therapy evaluation demonstrated further reduction [4.6+/-1.8 nmol/l (pre-RIT) vs. 3.8+/-2.9 nmol/l (post-RIT), P<0.05]. Patients receiving higher radiation doses to the testes (>=25 Gy) showed a greater reduction [4.7+/-1.6 nmol/l (pre-RIT) vs. 3.3+/-2.7 nmol/l (post-RIT), P<0.05] compared with patients receiving lower doses (<25 Gy), who showed no significant change in total testosterone levels. Conclusion: The testicular radiation absorbed dose varied highly among individual patients. Finally, patients receiving higher doses to the testes were more likely to show post-RIT suppression of testosterone levels.

  5. A systematic review of the use of rituximab as induction therapy in renal transplantation.

    PubMed

    Macklin, Philip S; Morris, Peter J; Knight, Simon R

    2015-04-01

    Rituximab is a B-lymphocyte depleting agent used to treat lymphoma and autoimmune diseases. There has been recent interest in its use both for management of highly-sensitised and ABO-incompatible recipients but also for induction therapy before transplantation. This systematic review evaluates the evidence for its use as part of induction protocols in ABO-compatible, non-sensitised recipients. 4 databases and 3 trial registries were searched for studies of the use of rituximab as part of induction protocols. The small number of identified studies precluded meta-analysis and thus a narrative review was conducted. 12 manuscripts met the inclusion criteria, relating to 5 individual studies. No significant improvements in patient and graft survival or acute rejection rates were identified with rituximab induction. A single small study reported a trend towards improved graft function with the addition of rituximab induction to a standard immunosuppressive regimen. Rituximab was not found to be associated with increased infectious complications in any study but concerns were raised over possible associations with leukopaenia and cardiovascular mortality. Overall, no convincing benefit of rituximab induction was found and some safety concerns were identified. The results of on-going trials are awaited but further studies may be required before we can draw firm conclusions regarding the efficacy and safety of rituximab in this setting. PMID:25555541

  6. In vivo B-cell depletion with rituximab for alternative donor hemopoietic SCT.

    PubMed

    Dominietto, A; Tedone, E; Soracco, M; Bruno, B; Raiola, A M; Van Lint, M T; Geroldi, S; Lamparelli, T; Galano, B; Gualandi, F; Frassoni, F; Bacigalupo, A

    2012-01-01

    We retrospectively analyzed 55 patients given a fixed dose of rituximab (200 mg) on day+5 after an alternative donor transplant, to prevent EBV DNA-emia; 68 alternative transplants who did not receive prophylactic rituximab served as controls. The two groups were comparable for donor type, and all patients received anti-thymocyte globulin in the conditioning regimen. Rituximab patients had a significantly lower rate of EBV DNA-emia 56 vs 85% (P=0.0004), a lower number of maximum median EBV copies (91 vs 1321/10(5) cells, P=0.003) and a significantly lower risk of exceeding 1000 EBV copies per 10(5)cells (14 vs 49%, P=0.0001). Leukocyte and lymphocyte counts were lower on day +50 and+100 in rituximab patients, whereas Ig levels were comparable. The cumulative incidence of grade II-IV acute GvHD was significantly reduced in rituximab patients (20 vs 38%, P=0.02). Chronic GvHD was comparable. There was a trend for a survival advantage for patients receiving rituximab (46 vs 40%, P=0.1), mainly because of lower transplant mortality (25 vs 37%, P=0.1). Despite the drawback of a retrospective study, these data suggest that a fixed dose of rituximab on day +5 reduces the risk of a high EBV load, and also reduces acute GvHD. PMID:21460867

  7. Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era

    PubMed Central

    Gisselbrecht, Christian; Glass, Bertram; Mounier, Nicolas; Singh Gill, Devinder; Linch, David C.; Trneny, Marek; Bosly, Andre; Ketterer, Nicolas; Shpilberg, Ofer; Hagberg, Hans; Ma, David; Brière, Josette; Moskowitz, Craig H.; Schmitz, Norbert

    2010-01-01

    Purpose Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown. Patients and Methods Patients with CD20+ DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT. Results The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001). Conclusion In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP. PMID:20660832

  8. Rituximab for the treatment of IgG4-related orbital disease: experience from five cases

    PubMed Central

    Wu, A; Andrew, N H; Tsirbas, A; Tan, P; Gajdatsy, A; Selva, D

    2015-01-01

    Purpose To review the clinical efficacy and safety of rituximab for treatment of IgG4-related orbital disease (IgG4-ROD). Design Retrospective multicentre interventional case series. Methods Chart review for five cases of biopsy-confirmed IgG4-ROD (IgG4+>10/HPF, ratio of IgG4+/IgG+>40%) treated with rituximab. Information retrieved included the dosing schedule, adverse events and the magnitude, temporality, and duration of the clinical response. Results All cases of IgG4-ROD were either steroid dependent or steroid resistant. Rituximab doses for induction therapy included two doses of 1000 mg at 2-weekly intervals, and four doses at 375 mg/m2 at weekly intervals. Two months after starting rituximab, three cases achieved complete clinical resolution and two cases achieved partial clinical resolution. Complete radiological resolution occurred in one case, and partial radiological resolution in three cases. Three cases received rituximab maintenance therapy and one case was commenced on mycophenolate. No relapse occurred during a mean follow-up of 33 months (range: 7–65 months). One disease relapse occurred when the dosing interval of rituximab maintenance therapy was extended to 6–monthly intervals; remission was swiftly achieved with rituximab reinduction therapy. The only adverse effects reported were one episode of fatigue lasting 1 week and two episodes of orbital discomfort. Conclusion Rituximab may be an effective treatment option for IgG4-ROD that is steroid dependent or steroid intolerant. Rituximab therapy resulted in swift clinical and radiological improvement, many months free of relapse, and few side effects. PMID:25341435

  9. Resolution of diarrhea in an immunocompromised patient with chronic norovirus gastroenteritis correlates with constitution of specific antibody blockade titer.

    PubMed

    Knoll, Bettina M; Lindesmith, Lisa C; Yount, Boyd L; Baric, Ralph S; Marty, Francisco M

    2016-08-01

    Norovirus gastroenteritis in immunocompromised hosts can result in a serious and prolonged diarrheal illness. We present a case of chronic norovirus disease during rituximab-bendamustine chemotherapy for non-Hodgkin's lymphoma. We show for the first time a correlation between norovirus strain-specific antibody blockade titers and symptom improvement in an immunocompromised host. PMID:26825307

  10. Hematologic toxicity in radioimmunotherapy: An evaluation of different predictive measures

    SciTech Connect

    Sgouros, G.; Divgi, C.; Scott, A.M.

    1996-05-01

    In essentially all cases of intravenously administered administered radiolabeled antibody, hematologic toxicity has limited the amount of radioactivity that may be administered. In this study 4 potential predictors of hematologic toxicity are evaluated: red marrow dose (RMD), whole-body dose (WBD), administered activity (AA), and administered activity per unit surface area (AASA). These were evaluated against 8 measures of hematologic toxicity: grade (G), time-to-nadir (TTN), and absolute and per cent drop in counts (ADC, %DC) for platelets (P) and white blood cells (W). Data from a phase I study of 29 patients with metastatic colon carcinoma and a total of 35 different antibody administrations of {sup 131}I-CC49 antibody were used in the analysis. Serum clearance kinetics were used to estimate RMD. A remainder-of-body term representing activity not in the red marrow was included in the RMD calculations. The whole-body dose was estimated as the product of whole-body cumulated activity, derived form survey meter measurements, and the whole-body to whole-body S-factor. All S-factors were obtained from MIRD Pamphlet 11. Patient surface area was estimated form each patient`s height and weight. Patients exhibiting accelerated clearance kinetics due to an immunologic response against the antibody (HAMA) were included in the analysis. The correlation coefficients, r, are listed in the table. All patients had been treated with 5-FU and leucovorin previously. When patients that has also been treated with mitomycin and/or alkylating agents were excluded from the analysis, the r values shown on the last line of the table were obtained for platelet toxicity grade. These results suggest that, although still poor, RMD may be a slightly better predictor of toxicity than other measures.

  11. Diagnosis of and therapy for solid tumors with radiolabeled antibodies and immune fragments

    SciTech Connect

    Carrasquillo, J.A.; Krohn, K.A.; Beaumier, P.; McGuffin, R.W.; Brown, J.P.; Hellstroem, K.E.; Hellstroem, I.; Larson, S.M.

    1984-01-01

    Antibodies which are directed against human tumor-associated antigens can potentially be used as carriers of radioactivity for in vivo diagnosis (radioimmunodetection) or treatment (radioimmunotherapy) of solid tumors, including colon, hepatoma, cholangiocarcinoma, and melanoma. Murine monoclonal antibodies (MOAB), produced by the hybridoma technique of Kohler and Milstein, are replacing conventional heterosera as sources of antibodies, because MOAB can be produced in large quantities as reproducible reagents with homogeneous binding properties. We have studied human melanoma using MOAB IgG and Fab fragments that recognize the human melanoma-associated antigens p97 and ''high-molecular-weight antigen''. Both antigens are found in the membrane of melanomas at much larger concentrations than in normal adult tissues. We have performed radioimmunodetection studies with whole immunoglobulin and have detected 88% of lesions greater than 1.5 cm. We have used Fab fragments for radioimmunotherapy and have found that large doses of radiolabeled antibodies (up to 342 mCi) can be repetitively given to patients without excessive end-organ toxicity. Two of three patients treated with high-dose radiolabeled antimelanoma Fab showed an effect from the treatment. Although both technical and biologic problems remain, the use of radiolabeled antibodies that are directed against tumor-associated antigens holds future promise as a new therapeutic approach to solid tumors that are resistant to conventional therapy.

  12. Rituximab maintenance after autologous stem cell transplantation prolongs response duration in non-naive rituximab follicular lymphoma patients: a single institution experience.

    PubMed

    Bourcier, J; Gastinne, T; Leux, C; Moreau, A; Bossard, C; Mahé, B; Blin, N; Dubruille, V; Touzeau, C; Voldoire, M; Guillaume, T; Peterlin, P; Gallas, P; Garnier, A; Maisonneuve, H; Moreau, P; Juge-Morineau, N; Jardel, H; Chevallier, P; Moreau, P; Le Gouill, S

    2016-08-01

    We retrospectively evaluated the role of rituximab (R) in maintenance treatment after autologous stem cell transplantation performed in patients with relapsed follicular lymphoma. We compared the outcome of 67 follicular lymphoma (FL) patients according to the use of rituximab maintenance (RM) or not. All patients received rituximab plus chemotherapy before autologous stem-cell transplantation (ASCT). Patients received median of two lines of prior therapy. The RM schedule was one injection of rituximab every 3 months for 2 years. Median follow-up is 4.6 years. The 3-year progression-free survival (PFS) after ASCT was 86 % with RM vs. 46 % without (p = 0.0045). Median is not reached in the RM arm vs. 31 months in non-RM arm. The 3-year OS was 96 % with RM vs. 78 % without (p = 0.059). The present monocentric study shows that 2 years of RM after ASCT significantly increases response duration for non-naive rituximab relapsed FL patients compared with observation. PMID:27297970

  13. Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    SciTech Connect

    Frost, Sophia; Frayo, Shani; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; Back, Tom; Fisher, Darrell R.; Press, Oliver W.

    2015-03-01

    Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.

  14. New antibody conjugates in cancer therapy.

    PubMed

    Govindan, Serengulam V; Goldenberg, David M

    2010-01-01

    Targeting of radiation, drugs, and protein toxins to cancers selectively with monoclonal antibodies (MAbs) has been a topic of considerable interest and an area of continued development. Radioimmunotherapy (RAIT) of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti-CD22 MAb, 90Y-epratuzumab. The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and preclinically. The area of drug-conjugated antibodies is progressing with encouraging data published for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The Dock-and-Lock platform technology has contributed to the design and the evaluation of complex antibody-cytokine and antibody-toxin conjugates. This review describes the advances made in these areas, with illustrations taken from advances made in the authors' institutions. PMID:20953556

  15. Beta emitters rhenium-188 and lutetium-177 are equally effective in radioimmunotherapy of HPV-positive experimental cervical cancer.

    PubMed

    Phaeton, Rebecca; Jiang, Zewei; Revskaya, Ekaterina; Fisher, Darrell R; Goldberg, Gary L; Dadachova, Ekaterina

    2016-01-01

    Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy-we performed RIT of experimental cervical cancer with Rhenium-188 ((188) Re) and Lutetium-177 ((177) Lu)-labeled mAb C1P5 to E6. The biodistribution of (188) Re- and (177) Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either (188) Re-C1P5 or (177) Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of (188) Re- and (177) Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both (177) Lu-C1P5 and (188) Re-C1P5. The dose to the liver was five times higher for (177) Lu-C1P5. The doses to the tumor were 259 and 181 cGy for (177) Lu-C1P5 and (188) Re-C1P5, respectively. RIT with either (177) Lu-C1P5 or (188) Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in (177) Lu-C1P5 group only and on day 10 it was observed in both (177) Lu-C1P5 and (188) Re-C1P5 groups. (188) Re- and (177) Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer. PMID:26625938

  16. Clinical responses to rituximab in a case of neuroblastoma with refractory opsoclonus myoclonus ataxia syndrome.

    PubMed

    Alavi, Samin; Kord Valeshabad, Ali; Moradveisi, Borhan; Aminasnafi, Ali; Arzanian, Mohammad Taghi

    2012-01-01

    Opsoclonus myoclonus ataxia syndrome (OMS) is a rare neurologic syndrome. In a high proportion of children, it is associated with neuroblastoma. The etiology of this condition is thought to be immune mediated. In children, immunotherapy with conventional treatments such as corticosteroids, intravenous immunoglobulin, adrenocorticotropic hormone, and even antiepileptic drugs has been tried. Recently rituximab has been used safely for refractory OMS in children with neuroblastoma. Our patient was a 3.5-year-old girl referred for ataxia and dancing eye movements starting since 1.5 years ago. She was diagnosed with neuroblastoma on imaging studies on admission. The OMS was refractory to surgical resection, chemotherapy, corticosteroids, and intravenous immunoglobulin. Patient received rituximab simultaneously with chemotherapy. The total severity score decreased by 61.1% after rituximab. Patient's ataxia markedly improved that she was able to walk independently after 6 months. Our case confirmed the clinical efficacy and safety of rituximab in a refractory case of OMS. PMID:23198199

  17. Expression and biological characterization of an anti-CD20 biosimilar candidate antibody

    PubMed Central

    Dorvignit, Denise; Palacios, Julio L.; Merino, Maylin; Hernández, Tays; Sosa, Katya; Casacó, Angel; López-Requena, Alejandro; Mateo de Acosta, Cristina

    2012-01-01

    The CD20 molecule is a non-glycosylated protein expressed mainly on the surface of B lymphocytes. In some pathogenic B cells, it shows an increased expression, thus becoming an attractive target for diagnosis and therapy. Rituximab is a chimeric antibody that specifically recognizes the human CD20 molecule. This antibody is indicated for the treatment of non-Hodgkin lymphomas and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. In this work, we describe the stable expression and biological evaluation of an anti-CD20 biosimilar antibody. While rituximab is produced in fed-batch culture of recombinant Chinese hamster ovary (CHO) cells, our biosimilar antibody expression process consists of continuous culture of recombinant murine NS0 myeloma cells. The ability of the purified biosimilar antibody to recognize the CD20 molecule on human tumor cell lines, as well as on peripheral blood mononuclear cells from humans and primates, was demonstrated by flow cytometry. The biosimilar antibody induced complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and apoptosis on human cell lines with high expression of CD20. In addition, this antibody depleted CD20-positive B lymphocytes from peripheral blood in monkeys. These results indicate that the biological properties of the biosimilar antibody compare favorably with those of the innovator product, and that it should be evaluated in future clinical trials. PMID:22647435

  18. Expression and biological characterization of an anti-CD20 biosimilar candidate antibody: a case study.

    PubMed

    Dorvignit, Denise; Palacios, Julio L; Merino, Maylin; Hernández, Tays; Sosa, Katya; Casaco, Angel; López-Requena, Alejandro; Mateo de Acosta, Cristina

    2012-01-01

    The CD20 molecule is a non-glycosylated protein expressed mainly on the surface of B lymphocytes. In some pathogenic B cells, it shows an increased expression, thus becoming an attractive target for diagnosis and therapy. Rituximab is a chimeric antibody that specifically recognizes the human CD20 molecule. This antibody is indicated for the treatment of non-Hodgkin lymphomas and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. In this work, we describe the stable expression and biological evaluation of an anti-CD20 biosimilar antibody. While rituximab is produced in fed-batch culture of recombinant Chinese hamster ovary (CHO) cells, our biosimilar antibody expression process consists of continuous culture of recombinant murine NS0 myeloma cells. The ability of the purified biosimilar antibody to recognize the CD20 molecule on human tumor cell lines, as well as on peripheral blood mononuclear cells from humans and primates, was demonstrated by flow cytometry. The biosimilar antibody induced complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and apoptosis on human cell lines with high expression of CD20. In addition, this antibody depleted CD20-positive B lymphocytes from peripheral blood in monkeys. These results indicate that the biological properties of the biosimilar antibody compare favorably with those of the innovator product, and that it should be evaluated in future clinical trials. PMID:22647435

  19. Retrospective analysis of rituximab therapy and splenectomy in childhood chronic and refractory immune thrombocytopenic purpura.

    PubMed

    Ay, Yilmaz; Karapinar, Tuba H; Oymak, Yesim; Toret, Ersin; Demirag, Bengu; Ince, Dilek; Ozcan, Esin; Moueminoglou, Nergial; Koker, Sultan A; Vergin, Canan

    2016-06-01

    Immune thrombocytopenic purpura (ITP) results from accelerated platelet destruction mediated by autoantibodies to platelet glycoproteins. Some patients with chronic ITP are refractory to all therapies [steroids, intravenous immunoglobulin (IVIG), anti-D and immunosuppresive drugs] and have chronic low platelet counts and episodic bleeding. We retrospectively evaluated the efficacy and safety of rituximab treatment and splenectomy in paediatric patients diagnosed with chronic and refractory ITP who were unresponsive to steroids, IVIG, cyclosporine and mycophenolate mofetil. Records of patients with chronic and refractory ITP in 459 patients with primary ITP who were followed up in our hospital from January 2005 to December 2014 were reviewed. Fifteen of patients received rituximab and/or applied splenectomy. Fifteen chronic ITP patients (10 boys, five girls) with a mean age of 10 years were enrolled in the study. Two of these patients were suffering from Evans syndrome. The median time since diagnosis of ITP was 10 years. The median follow-up duration after starting Rituximab and splenectomy were 13 and 9.5 months, respectively.None of the seven patients who were treated with rituximab achieved a response. A splenectomy was performed in six of the seven patients who had been treated with rituximab. Complete and partial responses were achieved in 67 and 33% of the patients, respectively. We evaluated the clinical characteristics and responses of chronic ITP patients who did not receive rituximab therapy and underwent a splenectomy. The success rate was 100% in the eight patients with chronic and refractory ITP. Rituximab therapy might not be beneficial for some children with severe chronic ITP who are refractory to standard agents. A splenectomy might be useful and preferable to rituximab. PMID:26656905

  20. High titers of anti-HBs prevent rituximab-related viral reactivation in resolved hepatitis B patient with non-Hodgkin's lymphoma.

    PubMed

    Cho, Yuri; Yu, Su Jong; Cho, Eun Ju; Lee, Jeong-Hoon; Kim, Tae Min; Heo, Dae Seog; Kim, Yoon Jun; Yoon, Jung-Hwan

    2016-06-01

    Rituximab, an anti-CD20 monoclonal antibody, is associated with an increased risk of hepatitis B virus (HBV) reactivation. This study aimed to determine the predictive factors for rituximab-related HBV reactivation in resolved hepatitis B patients, defined as HBsAg-negative, anti-HBc-positive, and undetectable HBV DNA. Among 840 consecutive patients with CD20-positive B-cell lymphoma who received rituximab-based chemotherapy from 2003 through 2014 at Seoul National University Hospital, 732 patients were excluded because either anti-HBc was not assessed or they were HBsAg-seropositive. This retrospective study included 108 resolved hepatitis B patients. During a median 33.5-month follow-up period, eight cases of HBV reactivation occurred only among the patients with low anti-HBs titers (<100 mIU/ml) at baseline and those who did not receive antiviral prophylaxis. Using multivariate analyses, antiviral prophylaxis and baseline anti-HBs titers were the protective factors for HBV reactivation (hazard ratio [HR], 0.90 and 0.95, respectively). Among those who did not receive antiviral prophylaxis, patients with high baseline anti-HBs (≥100 mIU/ml) experienced significantly lower risk of HBV reactivation (HR, 0.49; P = 0.006) than the patients with low baseline anti-HBs (<100 mIU/ml) whose cumulative HBV reactivation rates at 6 and 24 months after chemotherapy were 8.3% and 17.3%, respectively. High anti-HBs titer at baseline and antiviral prophylaxis prevented HBV reactivation, suggesting antiviral prophylaxis should be considered according to baseline anti-HBs titer. Meticulous follow-up for ALT and HBV DNA without antiviral prophylaxis might be possible for the patients with high baseline anti-HBs (≥100 mIU/ml). J. Med. Virol. 88:1010-1017, 2016. © 2015 Wiley Periodicals, Inc. PMID:26531242

  1. Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA

    PubMed Central

    Delfau-Larue, Marie-Hélène; de Leval, Laurence; Joly, Bertrand; Plonquet, Anne; Challine, Dominique; Parrens, Marie; Delmer, Alain; Salles, Gilles; Morschhauser, Franck; Delarue, Richard; Brice, Pauline; Bouabdallah, Reda; Casasnovas, Olivier; Tilly, Hervé; Gaulard, Philippe; Haioun, Corinne

    2012-01-01

    Background In angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20+ large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy. Design and Methods Twenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome. Results A complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median follow-up of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P<0.004) and the detection of circulating tumor cells (P=0.0019). Despite peripheral Epstein-Barr virus clearance after treatment, the viral load at diagnosis (>100 copy/μg DNA) was associated with shorter progression-free survival (P=0.06). Conclusions We report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20+ B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted. PMID:22371178

  2. Use of Rituximab in Children with Steroid- and Calcineurin-Inhibitor-Dependent Idiopathic Nephrotic Syndrome

    PubMed Central

    Ravani, Pietro; Ponticelli, Alessandro; Siciliano, Chiara; Fornoni, Alessia; Magnasco, Alberto; Sica, Felice; Bodria, Monica; Caridi, Gianluca; Wei, Changli; Belingheri, Mirco; Ghio, Luciana; Merscher-Gomez, Sandra; Edefonti, Alberto; Pasini, Andrea; Montini, Giovanni; Murtas, Corrado; Wang, Xiangyu; Muruve, Daniel; Vaglio, Augusto; Martorana, Davide; Pani, Antonello; Scolari, Francesco; Reiser, Jochen; Ghiggeri, Gian Marco

    2013-01-01

    In children with idiopathic nephrotic syndrome rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin-inhibitors. Long-term effects including number of repeated infusions to maintain remission are unknown. We treated with rituximab 46 consecutive children with idiopathic nephrotic syndrome lasting for at least one year (6.3±4.1 years), who were maintained in remission with oral prednisone and calcineurin inhibitors. They received 1–5 rituximab courses during a median follow-up of three years (range 1–5). Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and two-year-remission probabilities were respectively 20% and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months respectively following the first and subsequent courses. Time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20 or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Rituximab can be safely and repeatedly used as prednisone and calcineurin-inhibitor-sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further research is needed to identify patients who will benefit most from rituximab therapy. PMID:23739238

  3. Evaluation of a glycoengineered monoclonal antibody via LC-MS analysis in combination with multiple enzymatic digestion

    PubMed Central

    Liu, Renpeng; Giddens, John; McClung, Colleen M.; Magnelli, Paula E.; Wang, Lai-Xi; Guthrie, Ellen P.

    2016-01-01

    ABSTRACT Glycosylation affects the efficacy, safety and pharmacokinetics/pharmacodynamics properties of therapeutic monoclonal antibodies (mAbs), and glycoengineering is now being used to produce mAbs with improved efficacy. In this work, a glycoengineered version of rituximab was produced by chemoenzymatic modification to generate human-like N-glycosylation with α 2,6 linked sialic acid. This modified rituximab was comprehensively characterized by liquid chromatography-mass spectrometry and compared to commercially available rituximab. As anticipated, the majority of N-glycans were converted to α 2,6 linked sialic acid, in contrast to CHO-produced rituximab, which only contains α 2,3 linked sialic acid. Typical posttranslational modifications, such as pyro-glutamic acid formation at the N-terminus, oxidation at methionine, deamidation at asparagine, and disulfide linkages were also characterized in both the commercial and glycoengineered mAbs using multiple enzymatic digestion and mass spectrometric analysis. The comparative study reveals that the glycoengineering approach does not cause any additional posttranslational modifications in the antibody except the specific transformation of the glycoforms, demonstrating the mildness and efficiency of the chemoenzymatic approach for glycoengineering of therapeutic antibodies. PMID:26514686

  4. A mechanistic compartmental model for total antibody uptake in tumors

    PubMed Central

    Thurber, Greg M.; Dane Wittrup, K.

    2012-01-01

    Antibodies are under development to treat a variety of cancers, such as lymphomas, colon, and breast cancer. A major limitation to greater efficacy for this class of drugs is poor distribution in vivo. Localization of antibodies occurs slowly, often in insufficient therapeutic amounts, and distributes heterogeneously throughout the tumor. While the microdistribution around individual vessels is important for many therapies, the total amount of antibody localized in the tumor is paramount for many applications such as imaging, determining the therapeutic index with antibody drug conjugates, and dosing in radioimmunotherapy. With imaging and pretargeted therapeutic strategies, the time course of uptake is critical in determining when to take an image or deliver a secondary reagent. We present here a simple mechanistic model of antibody uptake and retention that captures the major rates that determine the time course of antibody concentration within a tumor including dose, affinity, plasma clearance, target expression, internalization, permeability, and vascularization. Since many of the parameters are known or can be estimated in vitro, this model can approximate the time course of antibody concentration in tumors to aid in experimental design, data interpretation, and strategies to improve localization. PMID:22974563

  5. Monoclonal antibodies in acute lymphoblastic leukemia

    PubMed Central

    O’Brien, Susan; Ravandi, Farhad; Kantarjian, Hagop

    2015-01-01

    With modern intensive combination polychemotherapy, the complete response (CR) rate in adults with acute lymphoblastic leukemia (ALL) is 80% to 90%, and the cure rate is 40% to 50%. Hence, there is a need to develop effective salvage therapies and combine novel agents with standard effective chemotherapy. ALL leukemic cells express several surface antigens amenable to target therapies, including CD20, CD22, and CD19. Monoclonal antibodies target these leukemic surface antigens selectively and minimize off-target toxicity. When added to frontline chemotherapy, rituximab, an antibody directed against CD20, increases cure rates of adults with Burkitt leukemia from 40% to 80% and those with pre-B ALL from 35% to 50%. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has resulted in marrow CR rates of 55% and a median survival of 6 to 7 months when given to patients with refractory-relapsed ALL. Blinatumomab, a biallelic T cell engaging the CD3-CD19 monoclonal antibody, also resulted in overall response rates of 40% to 50% and a median survival of 6.5 months in a similar refractory-relapsed population. Other promising monoclonal antibodies targeting CD20 (ofatumumab and obinutuzumab) or CD19 or CD20 and bound to different cytotoxins or immunotoxins are under development. Combined modalities of chemotherapy and the novel monoclonal antibodies are under investigation. PMID:25999456

  6. Innovative Monoclonal Antibody Therapies in Multiple Sclerosis

    PubMed Central

    Kieseier, Bernd C.

    2008-01-01

    The recent years have witnessed great efforts in establishing new therapeutic options for multiple sclerosis (MS), especially for relapsing–remitting disease courses. In particular, the application of monoclonal antibodies provide innovative approaches allowing for blocking or depleting specific molecular targets, which are of interest in the pathogenesis of MS. While natalizumab received approval by the US Food and Drug Administration and the European Medicines Agency in 2006 as the first monoclonal antibody in MS therapy, rituximab, alemtuzumab, and daclizumab were successfully tested for relapsing-remitting MS in small cohorts in the meantime. Here, we review the data available from these recent phase II trials and at the same time critically discuss possible pitfalls which may be relevant for clinical practice. The results of these studies may not only broaden our therapeutic options in the near future, but also provide new insights into disease pathogenesis. PMID:21180564

  7. Novel humanized anti-CD20 antibody BM-ca binds to a unique epitope and exerts stronger cellular activity than others

    PubMed Central

    Kobayashi, Hideaki; Matsunaga, Yuka; Uchiyama, Yumiko; Nagura, Kenji; Komatsu, Yasuhiko

    2013-01-01

    Cellular activity of BM-ca, a novel humanized anti-CD20 antibody, was quantitatively compared with that of two other anti-CD20 antibodies used for clinical practice, rituximab and ofatumumab. The results of a complement-dependent cytotoxicity (CDC) assay revealed that the strongest antibody was ofatumumab, followed by BM-ca, with rituximab being the weakest. Ofatumumab and BM-ca were effective not only against rituximab-sensitive SU-DHL-4 cells but also against rituximab-resistant RC-K8 cells. In an antibody-dependent cell-mediated cytotoxicity (ADCC) assay, although the effective concentrations against SU-DHL-4 cells were almost the same among these three antibodies, the maximum cytotoxic level was the highest for BM-ca. In an anti-cell proliferation assay using SU-DHL-4 cells, BM-ca was the most effective and ofatumumab, the weakest. Against RC-K8 cells, only BM-ca was effective. When combined with each of four cancer chemotherapeutics (prednisolone, vincristine, hydroxydaunorubicin, and cisplatin), BM-ca exerted the most effective combinatorial anti-cell proliferation activity. To assess the in vivo effect of BM-ca, we intravenously administered BM-ca into cynomolgus monkeys and found that the peripheral B-cell levels did not decrease in half of the animals. Sequencing of cDNA encoding CD20 of cynomolgus monkeys revealed that the responders and nonresponders had Leu/Pro (hetero) and Leu/Leu (homo) at amino acid (a.a.) position 160, respectively, suggesting that the epitope recognized by BM-ca was around this a.a. By analyzing reactivity to synthetic peptides, the epitope recognized by BM-ca was estimated to be a.a.'s 156–166, not shared with rituximab and ofatumumab. These results suggest BM-ca to be a promising anti-CD20 antibody having superior properties and recognizing a unique epitope. PMID:23634281

  8. Antibody-mediated rejection after ABO-incompatible pediatric living donor liver transplantation for propionic acidemia: A case report.

    PubMed

    Honda, Masaki; Sakamoto, Seisuke; Sakamoto, Rieko; Matsumoto, Shirou; Irie, Tomoaki; Uchida, Koushi; Shimata, Keita; Kawabata, Seiichi; Isono, Kaori; Hayashida, Shintaro; Yamamoto, Hidekazu; Endo, Fumio; Inomata, Yukihiro

    2016-09-01

    We herein present the case of a four-yr-old boy with PA who developed AMR after ABO-incompatible LDLT despite undergoing B cell desensitization using rituximab. Although the CD19+ lymphocyte count decreased to 0.1% nine days after the administration of rituximab, he developed a high fever which was accompanied by arthralgia due to a streptococcal infection 13 days after rituximab prophylaxis. After the clearance of the infection, he underwent ABO-incompatible LDLT 36 days after the administration of rituximab. The CD19+ lymphocyte count just prior to LDLT was 1.2%. He developed AMR five days after LDLT, and the antidonor-type IgM and IgG antibody titers increased to 1:1024 and 1:1024, respectively. He was treated by plasma exchange, IVIG, steroid pulse therapy, and rituximab re-administration; however, his liver dysfunction continued. Despite intensive treatment, he died due to complicated abdominal hernia, acute renal failure, and ARDS. This case suggests that a streptococcal infection may induce the activation of innate immune responses; thus, additional desensitization therapy should be considered prior to ABO-incompatible LDLT if B cell reactivation is suspected. PMID:27436684

  9. Cold Autoimmune Hemolytic Anemia due to High-grade non Hodgkin's B cell Lymphoma with Weak Response to Rituximab and Chemotherapy Regimens

    PubMed Central

    Nazel Khosroshahi, Behzad; Jafari, Mohammad; Vazini, Hossein; Ahmadi, Alireza; Shams, Keivan; Kholoujini, Mahdi

    2015-01-01

    Autoimmune hemolytic anemia (AIHA) is characterized by shortening of red blood cell (RBC) survival and the presence of autoantibodies directed against autologous RBCs. Approximately 20% of autoimmune hemolytic anemia cases are associated with cold-reactive antibody. About half of patients with AIHA have no underlying associated disease; these cases are termed primary or idiopathic. Secondary cases are associated with underlying diseases or with certain drugs. We report herein a rare case of cold autoimmiune hemolytic anemia due to high-grade non-Hodgkin's lymphoma of B-cell type with weak response to rituximab and chemotherapy regimens. For treatment B cell lymphoma, Due to lack of treatment response, we used chemotherapy regimens including R- CHOP for the first time, and then Hyper CVAD, R- ICE and ESHAP were administered, respectively. For treatment of autoimmune hemolytic anemia, we have used the corticosteroid, rituximab, plasmapheresis and blood transfusion and splenectomy. In spite of all attempts, the patient died of anemia and aggressive lymphoma nine months after diagnosis. To our knowledge, this is a rare report from cold autoimmune hemolytic anemia in combination with high-grade non-Hodgkin's lymphoma of B-cell type that is refractory to conventional therapies. PMID:26261701

  10. Radioimmunotherapy for non-Hodgkin's lymphoma: A review for radiation oncologists

    SciTech Connect

    Macklis, Roger M. . E-mail: macklir@ccf.org; Pohlman, Brad

    2006-11-01

    Purpose: The aim of this study was to review advances in radioimmunotherapy (RIT) for non-Hodgkin's lymphoma (NHL) and to discuss the role of Radiation oncologist in administering this important new form of biologically targeted radiotherapy. Methods and Materials: A review of articles and abstracts on the clinical efficacy, safety, and radiation safety of yttrium Y 90 ({sup 9}Y) ibritumomab tiuxetan (Zevalin) and iodine I 131 tositumomab (Bexxar) was performed. Results: The clinical efficacy of RIT in NHL has been shown in numerous clinical trials of {sup 9}Y ibritumomab tiuxetan and {sup 131}I tositumomab. Both agents have produced significant responses in patients with low-grade, follicular, or transformed NHL, including patients with disease that had not responded or had responded poorly to previous chemotherapy or immunotherapy. Reversible toxicities such as neutropenia, thrombocytopenia, and anemia are the most common adverse events with both agents. Conclusions: Radioimmunotherapy is safe and effective in many patients with B-cell NHL. {sup 9}Y ibritumomab tiuxetan and {sup 131}I tositumomab can produce clinically meaningful and durable responses even in patients in whom chemotherapy has failed. Treatment with RIT requires a multispecialty approach and close communication between Radiation oncologist and other members of the treatment team. Radiation oncologist plays an important role in treating patients with RIT and monitoring them for responses and adverse events after treatment.

  11. Monte Carlo Calculation of Radioimmunotherapy with 90Y-, 177Lu-, 131I-, 124I-, and 188Re-Nanoobjects: Choice of the Best Radionuclide for Solid Tumour Treatment by Using TCP and NTCP Concepts

    PubMed Central

    Lucas, S.; Feron, O.; Gallez, B.; Masereel, B.; Michiels, C.; Vander Borght, T.

    2015-01-01

    Radioimmunotherapy has shown that the use of monoclonal antibodies combined with a radioisotope like 131I or 90Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of 90Y labelled to each antibody or nanoobject could be a solution to improve treatment output. It now seems important to assess the treatment output and toxicity when radionuclides such as 90Y, 177Lu, 131I, 124I, and 188Re are used. Tumour control probability (TCP) and normal tissue complication probability (NTCP) curves versus the number of radionuclides per nanoobject were computed with MCNPX to evaluate treatment efficacy for solid tumours and to predict the incidence of surrounding side effects. Analyses were carried out for two solid tumour sizes of 0.5 and 1.0 cm radius and for nanoobject (i.e., a radiolabelled antibody) distributed uniformly or nonuniformly throughout a solid tumour (e.g., Non-small-cell-lung cancer (NSCLC)). 90Y and 188Re are the best candidates for solid tumour treatment when only one radionuclide is coupled to one carrier. Furthermore, regardless of the radionuclide properties, high values of TCP can be reached without toxicity if the number of radionuclides per nanoobject increases. PMID:26136812

  12. Monoclonal Antibodies.

    ERIC Educational Resources Information Center

    Killington, R. A.; Powell, K. L.

    1984-01-01

    Monoclonal antibodies have provided an exciting addition to the "armory" of the molecular biologist and immunologist. This article discusses briefly the concept of, techniques available for, production of, and possible uses of monoclonal antibodies. (Author)

  13. Antimitochondrial antibody

    MedlinePlus

    ... antibodies (AMA) are substances ( antibodies ) that form against mitochondria. The mitochondria are an important part of cells. They are ... often, in people with other kinds of liver disease and some autoimmune diseases. Risks Risks for having ...

  14. 2nd PEGS Annual Symposium on Antibodies for Cancer Therapy

    PubMed Central

    Ho, Mitchell; Royston, Ivor; Beck, Alain

    2012-01-01

    The 2nd Annual Antibodies for Cancer Therapy symposium, organized again by Cambridge Healthtech Institute as part of the Protein Engineering Summit, was held in Boston, USA from April 30th to May 1st, 2012. Since the approval of the first cancer antibody therapeutic, rituximab, fifteen years ago, eleven have been approved for cancer therapy, although one, gemtuzumab ozogamicin, was withdrawn from the market.  The first day of the symposium started with a historical review of early work for lymphomas and leukemias and the evolution from murine to human antibodies. The symposium discussed the current status and future perspectives of therapeutic antibodies in the biology of immunoglobulin, emerging research on biosimilars and biobetters, and engineering bispecific antibodies and antibody-drug conjugates. The tumor penetration session was focused on the understanding of antibody therapy using ex vivo tumor spheroids and the development of novel agents targeting epithelial junctions in solid tumors. The second day of the symposium discussed the development of new generation recombinant immunotoxins with low immunogenicity, construction of chimeric antigen receptors, and the proof-of-concept of ‘photoimmunotherapy’. The preclinical and clinical session presented antibodies targeting Notch signaling and chemokine receptors.  Finally, the symposium discussed emerging technologies and platforms for therapeutic antibody discovery. PMID:22864478

  15. Rituximab for subcutaneous delivery: Clinical management principles from a nursing perspective.

    PubMed

    Carlson, Julia; Cox, Keith; Bedwell, Kylie; Ku, Mathew

    2015-12-01

    Nurses play an integral role in administering treatments to patients with non-Hodgkin's lymphomas. Intravenous (IV) rituximab was approved by the Australian Therapeutic Goods Administration in 1998, and a novel subcutaneous (SC) formulation was approved in 2014. Fixed-dose SC rituximab is highly concentrated; co-formulation with a fully human recombinant vorhyaluronidase alfa enzyme helps overcome the physiological barriers of the SC space, facilitating drug dispersion. Despite a different pharmacokinetic profile to the IV preparation, SC rituximab demonstrates a comparable efficacy/safety profile. Most frequently occurring rituximab-related adverse events include neutropenia, nausea and constipation, and administration-related reactions are more frequent with the SC preparation. Compared with IV, SC delivery reduces treatment times and nurse workload, and patients report greater comfort and convenience. This article sets out nursing considerations for optimal administration of SC rituximab, including premedication, drug handling/preparation, injection technique, after-care and management of adverse events, particularly administration-related reactions. PMID:26681664

  16. Successful rituximab treatment in an elderly patient with recurrent thrombotic thrombocytopenic purpura.

    PubMed

    Matsubara, Etsuko; Yamanouchi, Jun; Hato, Takaaki; Takeuchi, Kazuto; Niiya, Toshiyuki; Yasukawa, Masaki

    2016-07-01

    An 81-year-old man presenting with fever, neurological symptoms, thrombocytopenia, and hemolytic anemia was diagnosed with acquired idiopathic thrombotic thrombocytopenic purpura (TTP). His disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity was <1% and the ADAMTS13 inhibitor titer was 3.2 BU/ml. He received plasma exchange and steroid administration until remission was achieved. Seven months later, he suffered from paralysis of the right hand, hemolytic anemia, and thrombocytopenia. We confirmed TTP recurrence based on ADAMTS13 activity <1% and an ADAMTS13 inhibitor titer of 19.4 BU/ml. Four infusions of rituximab were administered in addition to plasma exchange and steroid pulse therapy. Platelet count recovery was observed within 5 days. No severe side effects related to rituximab occurred. Although rituximab has not been approved for TTP in Japan, we report the efficacy and safety of rituximab in an elderly patient with recurrent TTP. We suggest that rituximab therapy should be started as soon as possible for recurrent TTP in patients with high titers of ADAMTS13 inhibitor. PMID:27498731

  17. Radioimmunotherapy of micrometastases in lung with vascular targeted 213Bi.

    PubMed

    Kennel, S J; Boll, R; Stabin, M; Schuller, H M; Mirzadeh, S

    1999-04-01

    A model system has been used to test the efficacy of vascular targeting of alpha-particle emitter 213Bi for therapy of small, 'artificial' metastases in mouse lung. Specific monoclonal antibody (mAb) 201 B was used to deliver greater than 30% of the injected dose to lung where tumours had developed due to intravenous injection of cells. Specific 213Bi-mAb 201B treatment of BALB/c mammary carcinoma EMT-6 tumours in lung resulted in a dose-dependent destruction of tumours and an extended lifespan of treated animals relative to controls. Significant reduction of lung tumour burden was noted in animals treated with 0.93 MBq injected dose or as little as 14 Gy absorbed dose to the lung. Animals treated with higher doses (2.6-6.7 MBq) had nearly complete cure of lung tumours but eventually died of lung fibrosis induced by the treatment. Four other tumour cell types were studied: murine Line 1 lung carcinomas in syngeneic BALB/c mice, rat IC-12 tracheal carcinoma growing in severe combined immune deficient (SCID) mice, and two human tumours--epidermoid carcinoma A431 and lung carcinoma A549--growing in SCID mice. In all cases, the number of lung tumour colonies was reduced in animals treated with specific, labelled mAb relative to those in animals treated with control 213Bi MAb or EDTA complexed 213Bi. Tumours treated in immunodeficient SCID mice were partially destroyed or at least retarded in growth, but ultimately regrew and proved fatal, indicating that an intact immune function is necessary for complete cure. The data show that the short-lived alpha-particle emitter 213Bi can be effectively targeted to lung blood vessels and that tumour cells growing in the lung are killed. The mechanism may involve direct killing of tumour cells from alpha-particle irradiation, killing through destruction of blood supply to the tumour, or a combination of the two. PMID:10389994

  18. Radioimmunotherapy of micrometastases in lung with vascular targeted213Bi

    PubMed Central

    Kennel, S J; Boll, R; Stabin, M; Schuller, H M; Mirzadeh, S

    1999-01-01

    A model system has been used to test the efficacy of vascular targeting of α-particle emitter213Bi for therapy of small, ‘artificial’ metastases in mouse lung. Specific monoclonal antibody (mAb) 201B was used to deliver greater than 30% of the injected dose to lung where tumours had developed due to intravenous injection of cells. Specific213Bi-mAb 201B treatment of BALB/c mammary carcinoma EMT-6 tumours in lung resulted in a dose-dependent destruction of tumours and an extended lifespan of treated animals relative to controls. Significant reduction of lung tumour burden was noted in animals treated with 0.93 MBq injected dose or as little as 14 Gy absorbed dose to the lung. Animals treated with higher doses (2.6–6.7 MBq) had nearly complete cure of lung tumours but eventually died of lung fibrosis induced by the treatment. Four other tumour cell types were studied: murine Line 1 lung carcinomas in syngeneic BALB/c mice, rat IC-12 tracheal carcinoma growing in severe combined immune deficient (SCID) mice, and two human tumours – epidermoid carcinoma A431 and lung carcinoma A549 – growing in SCID mice. In all cases, the number of lung tumour colonies was reduced in animals treated with specific, labelled mAb relative to those in animals treated with control213Bi MAb or EDTA complexed213Bi. Tumours treated in immunodeficient SCID mice were partially destroyed or at least retarded in growth, but ultimately regrew and proved fatal, indicating that an intact immune function is necessary for complete cure. The data show that the short-lived α-particle emitter213Bi can be effectively targeted to lung blood vessels and that tumour cells growing in the lung are killed. The mechanism may involve direct killing of tumour cells from α-particle irradiation, killing through destruction of blood supply to the tumour, or a combination of the two. © 1999 Cancer Research Campaign PMID:10389994

  19. Rituximab as maintenance therapy for ANCA associated vasculitis: how, when and why?

    PubMed

    Alba, Marco A; Flores-Suárez, Luis Felipe

    2016-01-01

    ANCA-associated vasculitides (AAV) are chronic autoimmune diseases characterized by inflammation and destruction of small vessels. Rituximab is now licensed for use as a remission-induction agent in the treatment of these disorders. During recent years, several non-controlled studies have suggested that rituximab may be of value in maintaining disease remission in AAV. In these series, 3 techniques have been tried: "watch-and-wait", repeated cycles in fixed intervals, or administration based on proposed biomarkers. More importantly, the results of the MAINRITSAN trial showed that this anti-CD20 agent is superior to azathioprine for preventing major relapses in AAV. This review summarizes current information regarding the effectiveness, timing, dosing, duration and safety of rituximab as a valid option for remission maintenance. PMID:26255570

  20. Rituximab treatment for Epstein-Barr virus DNAemia after alternative-donor hematopoietic stem cell transplantation.

    PubMed

    Coppoletta, Stefania; Tedone, Elisabetta; Galano, Barbara; Soracco, Monica; Raiola, Anna Maria; Lamparelli, Teresa; Gualandi, Francesca; Bregante, Stefania; Ibatici, Adalberto; di Grazia, Carmen; Dominietto, Alida; Varaldo, Riccardo; Bruno, Barbara; Frassoni, Francesco; Van Lint, Maria Teresa; Bacigalupo, Andrea

    2011-06-01

    We report 55 patients undergoing an alternative-donor hematopoietic stem cell transplantation (HSCT) who developed Epstein-Barr virus (EBV) DNAemia, with >1000 EBV copies/10(5) peripheral blood mononuclear cells (PBMCs), and were treated with rituximab (375 mg/m(2)). The median patient age was 47 years (range, 20-65 years), and graft sources were mismatched family members (n = 4), unrelated donors (n = 46), and unrelated cord blood (n = 5). The conditioning regimen included antithymocyte globulin (ATG) in all patients. The median time to development of EBV DNAemia was day 27 post-HSCT (range, day 5 to day 242), with a median of 60 EBV copies/10(5) PBMCs (range, 1-5770 copies/10(5) PBMCs). The number of EBV copies was reduced to <1000/10(5) PBMCs on day +7 after initiation of rituximab therapy in 51% of the patients, on day +14 in 73% of the patients, and on +21 in 92% of the patients. Overall, 50 of 55 patients (91%) cleared EBV after one dose (n = 25) or more than one dose (n = 25) of rituximab. Factors predicting transplantation-related mortality (TRM) in multivariate analysis were a reduction to <1000 EBV copies/10(5) PBMCs by day +7 of treatment (relative risk [RR], 0.2; P = .01) and disease phase in remission (RR, 0.3; P = .05). TRM was 23% in the 40 patients with none or one of the negative predictors and 60% in the 15 patients with both negative predictors (P = .001). Of these latter 15 patients, 3 developed clinical posttransplantation lymphoproliferative disorder (PTLD). All 3 of these patients had a high EBV load on day +7 of rituximab therapy. This study confirms the effectiveness of rituximab in controlling EBV DNAemia in patients undergoing allogeneic HSCT. Patients with increasing EBV copies despite rituximab therapy are at high risk for EBV PTLD and may be considered for alternative therapies. PMID:20950702

  1. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma

    PubMed Central

    Micallef, Ivana N. M.; Maurer, Matthew J.; Wiseman, Gregory A.; Nikcevich, Daniel A.; Kurtin, Paul J.; Cannon, Michael W.; Perez, Domingo G.; Soori, Gamini S.; Link, Brian K.; Habermann, Thomas M.

    2011-01-01

    Approximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m2 intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821. PMID:21673350

  2. Immunosuppression associated with novel chemotherapy agents and monoclonal antibodies.

    PubMed

    Morrison, Vicki A

    2014-11-15

    The introduction of novel agents to the therapeutic armamentarium for oncologic, rheumatologic, and neurologic disorders has resulted in major clinical advances. These agents impact immune function, resulting in a discrete spectrum of infectious complications. Purine analogues and alemtuzumab alter cell-mediated immunity, resulting in opportunistic viral/fungal infections. Herpes zoster incidence increases with bortezomib. Hepatitis B reactivation may occur with rituximab. Cases of progressive multifocal leukoencephalopathy have occurred following monoclonal antibody therapy. Tumor necrosis factor-α inhibitor therapy is complicated by tuberculosis reactivation and fungal infections. We summarize the impact of these therapies on pathogenesis and spectrum of infection complicating their usage. PMID:25352632

  3. Monoclonal Antibodies in Cancer Therapy: Mechanisms, Successes and Limitations

    PubMed Central

    Coulson, A; Levy, A; Gossell-Williams, M

    2014-01-01

    ABSTRACT Rituximab was the first chemotherapeutic monoclonal antibody (CmAb) approved for clinical use in cancer therapeutics in 1997 and has significantly improved the clinical outcomes in non-Hodgkin's lymphoma. Since then, numerous CmAbs have been developed and approved for the treatment of various haematologic and solid human cancers. In this review, the classification, efficacy and significantly reduced toxicity of CmAbs available for use in the United States of America are presented. Finally, the limitations of CmAbs and future considerations are explored. PMID:25803383

  4. Conditioning with α-emitter based radioimmunotherapy in canine allogeneic hematopoietic cell transplantation

    PubMed Central

    Kornblit, Brian; Chen, Yun; Sandmaier, Brenda M.

    2012-01-01

    With the introduction of nonmyeloablative conditioning, hematopoietic cell transplantation (HCT) has become a viable treatment option for patients who due to age or comorbidities are ineligible for high dose conditioning. However, relapse and toxicities are still major problems in HCT. Radioimmunotherapy (RIT)-based conditioning is a promising approach that has the ability to specifically target radiation to hematopoietic cells. The most widely investigated isotopes are the β-emitters, but because of long path lengths and low linear energy transfer, α-emitters which have more favorable physical characteristics, might prove to be a better alternative. In the current study we have investigated the efficacy and safety of α-emitter based RIT as the only form of conditioning in a preclinical model of canine allogeneic HCT. PMID:22772070

  5. Low incidence of radionecrosis in children treated with conventional radiation therapy and intrathecal radioimmunotherapy.

    PubMed

    Kramer, Kim; Pandit-Taskar, Neeta; Zanzonico, Pat; Wolden, Suzanne L; Humm, John L; DeSelm, Carl; Souweidane, Mark M; Lewis, Jason S; Cheung, Nai-Kong V

    2015-06-01

    Radionecrosis is a potentially devastating complication of external beam radiotherapy (XRT). Intraventricular compartmental radioimmunotherapy (cRIT) using (131)I-3F8 or (131)I-8H9 can eradicate malignant cells in the CSF. The incidence of radionecrosis using cRIT (131)I based intraventricular radioimmunotherapy, when used alone or in combination with conventional craniospinal CSI-XRT is unknown. We retrospectively analyzed the incidence of radionecrosis in two cohorts of pediatric patients treated with both CSI-XRT and cRIT at MSKCC since 2003: patients with metastatic CNS neuroblastoma (NB) and medulloblastoma (MB). 94 patients received both CSI-XRT and cRIT, two received cRIT alone, median follow up 41.5 months (6.5-124.8 months). Mean CSI-XRT dose was 28 Gy (boost to the primary tumor site up to 54 Gy) in the MB cohort, and CSI XRT dose 18-21 Gy (boost to 30 Gy for focal parenchymal mass) in the NB cohort. For MB patients, 20 % had focal re-irradiation for a second or more subsequent relapse, mean repeat-XRT dose was 27.5 Gy; seven patients with NB had additional focal XRT. Median CSF cRIT dose was 18.6 Gy in the MB cohort and 32.1 in the NB cohort. One asymptomatic patient underwent resection of 0.6-cm hemorrhagic periventricular white-matter lesion confirmed to be necrosis and granulation tissue, 2.5 years after XRT. The risk of radionecrosis in children treated with XRT and cRIT appears minimal (~1 %). No neurologic deficits secondary to radionecrosis have been observed in long-term survivors treated with both modalities, including patients who underwent re-XRT. Administration of cRIT may safely proceed in patients treated with conventional radiotherapy without appearing to increase the risk of radionecrosis. PMID:25944385

  6. Radioimmunotherapy in the multimodality treatment of hepatocellular carcinoma with reference to second-look resection

    SciTech Connect

    Tang, Z.Y.; Liu, K.D.; Bao, Y.M.; Lu, J.Z.; Yu, Y.Q.; Ma, Z.C.; Zhou, X.D.; Yang, R.; Gan, Y.H.; Lin, Z.Y. )

    1990-01-15

    Experimental study using nude mice human hepatocellular carcinoma (HCC) xenograft indicated that the combination treatment with iodine 131 (131I)-anti-human HCC isoferritin (131I-isoFtAb), cisplatin, and mixed bacterial vaccine (MBV) yielded better inhibition rate as compared with double combination or 131I-isoFtAb alone. Based on these findings, 25 patients with surgically proven nonresectable and pathologically proven HCC have been treated by radioimmunotherapy using 131I-isoFtAb intrahepatic arterial infusion as a part of multimodality treatment. Of the 25 patients, seven (28.0%) received second-look resection after marked shrinkage of tumor. The 1-year survival was 52.5% (12/23) and 2-year survival 27.7% (five of 18) in the entire series. Of the five patients with 2-year survival, four were in the second-look resection group. Patients with tumor less than or equal to 8 cm showed higher second-look resection rate (62.5% versus 11.8%) and 1-year survival (85.7% versus 37.5%) as compared with tumor greater than 8 cm. Mixed bacterial vaccine as adjuvant immunotherapy seemed effective to prolong survival. The 2-year survival was higher in patients with second-look resection as compared with those without (75.0% versus 14.3%). Thus, radioimmunotherapy using 131I-isoFtAb might be one of the modalities of choice, particularly in the conversion of nonresectable to resectable HCC in a well-designed multimodality treatment regimen.

  7. Chemoenzymatic Glyco-engineering of Monoclonal Antibodies.

    PubMed

    Giddens, John P; Wang, Lai-Xi

    2015-01-01

    Monoclonal antibodies (mAbs) are an important class of therapeutic glycoproteins widely used for the treatment of cancer, inflammation, and infectious diseases. Compelling data have shown that the presence and fine structures of the conserved N-glycans at the Fc domain can profoundly affect the effector functions of antibodies. However, mAbs are usually produced as mixtures of Fc glycoforms and the control of glycosylation to a favorable, homogeneous status in various host expression systems is still a challenging task. In this chapter, we describe a detailed procedure of chemoenzymatic glyco-engineering of monoclonal antibodies, using rituximab (a therapeutic monoclonal antibody) as a model system. The protocol includes the deglycosylation of a mAb by an endoglycosidase (such as wild type EndoS) to remove the heterogeneous Fc N-glycans, leaving only the innermost GlcNAc or the core-fucosylated GlcNAc at the glycosylation site. Then the deglycosylated IgG serves as an acceptor for an endoglycosidase-catalyzed transglycosylation to add a desired N-glycan to the GlcNAc acceptor to reconstitute a defined, homogeneous natural glycoform of IgG, using a glycosynthase mutant as the enzyme and activated glycan oxazoline as the donor substrate. A semi-synthesis of sialylated and asialylated biantennary N-glycan oxazolines is also described. This detailed procedure can be used for the Fc glycosylation remodeling of other mAbs to provide homogeneous Fc glycoforms for various applications. PMID:26082235

  8. Risk factors for developing infusion reaction after rituximab administration in patients with B-cell non-Hodgkin's lymphoma.

    PubMed

    Tachi, T; Yasuda, M; Usui, K; Umeda, M; Nagaya, K; Osawa, T; Ichihashi, A; Noguchi, Y; Goto, H; Kasahara, S; Takahashi, T; Goto, C; Teramachi, H

    2015-10-01

    Rituximab (RTX), a monoclonal antibody against CD20, is known to cause fewer side effects than conventional anti-cancer drugs; however, infusion reaction (IR), which is specific to monoclonal antibody therapy, is frequently triggered by RTX. Therefore, we designed this study to identify risk factors based on clinical test values for developing IR after RTX administration. Eighty-nine patients with B-cell non-Hodgkin's lymphoma who had received RTX for the first time between February 2010 and March 2013, at the Gifu Municipal Hospital were enrolled as subjects. Analysis of data was conducted for 87 patients, after excluding patients whose data were missing. Univariate analysis showed significant differences in the number of patients exhibiting a soluble interleukin-2 receptor (sLL-2R) level > 2,000 U/L and hemoglobin (Hb) < lower standard limit (LSL) between the IR and non-IR groups. Multivariate analysis showed significant differences with respect to slL-2R > 2,000 U/L [odds ratio (OR), 4.463; 95% confidence interval (Cl), 1.262-15.779; P = 0.020], Hb < LSL [OR, 3.568; 95% CI, 1.071-11.890; P = 0.038], and steroid administration [OR, 0.284; 95% Cl, 0.094-0.852; P = 0.025]. Our findings show that sIL-2R > 2,000 U/L, Hb < LSL, and a lack of steroid premedication are risk factors for developing IR following RTX treatment. PMID:26601425

  9. t(11;18)(q21;q21)-positive advanced-stage MALT lymphoma associated with monoclonal gammopathy: resistance to rituximab or rituximab-containing chemotherapy.

    PubMed

    Ohno, Hitoshi; Isoda, Kotaro

    2008-11-01

    Here we describe two cases of mucosa-associated lymphoid tissue (MALT) lymphoma with monoclonal immunoglobulins (Igs). The first case was a 77-year-old man with primary lymphoma of the lung. Immunoelectrophoresis detected IgM-kappa in serum and kappa light chain excretion into urine. Three months after treatment with single-agent rituximab, a large amount of pleural fluid was found to have accumulated. The fluid contained CD5(-), CD10(-), CD19(+), CD38(+) and CD138(-/+) lymphoma cells with lymphoplasmacytoid appearance. Although a small fraction of the cells were CD20(+), the majority of the lymphoma cells were negative and expressed surface-membrane IgM-kappa at low levels. The cells possessed a karyotype of 46, XY, t(11;18)(q21;q21). The second case was a 55-year-old man who underwent total gastrectomy due to gastric perforation. Surgical specimens demonstrated the histopathological features of MALT lymphoma associated with plasma cell differentiation. The lymphoma cells had a 46, XY, t(11;18)(q21;q21) karyotype. Monoclonal Igs detected were serum IgA (M)-kappa and urinary kappa light chain. The patient was subsequently treated with six cycles of R-CVP (rituximab, cyclophosphamide, vincristine and prednisolone) ; however, serum monoclonal Ig levels were not affected. The lymphoma cells in both cases may have contained two populations, a rituximab-sensitive CD20(+) population and a rituximab-resistant population that had differentiated into the Ig-secreting plasma cell stage. PMID:19039196

  10. A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus–Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: the STARMEN study

    PubMed Central

    Rojas-Rivera, Jorge; Fernández-Juárez, Gema; Ortiz, Alberto; Hofstra, Julia; Gesualdo, Loreto; Tesar, Vladimir; Wetzels, Jack; Segarra, Alfons; Egido, Jesus; Praga, Manuel

    2015-01-01

    Background Patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome have a high risk of progression to end-stage renal disease. The Ponticelli protocol (steroids with alkylating agents) is the most effective immunosuppressive therapy for this condition, but it has severe adverse effects. Tacrolimus and rituximab have demonstrated efficacy for remission of nephrotic syndrome in MN with a safer profile. However, the published evidence is largely based on small or short-term observational studies, historical cohorts, comparisons with conservative therapy or clinical trials without appropriate control groups, and there is no head-to-head comparison with the Ponticelli protocol. Methods The STARMEN randomized clinical trial will compare the efficacy of sequential tacrolimus–rituximab therapy with a modified Ponticelli protocol (steroids plus cyclophosphamide). The trial will also evaluate the role of antibodies against the M-type phospholipase A2 receptor (anti-PLA2R) and other antibodies as markers of response to treatment and long-term prognosis. Results The trial has already started with 23 patients having been enrolled as of 1 April 2015, an estimated 21.7% of the estimated sample. PMID:26413273

  11. A phase 2 study of Rituximab-Bendamustine and Rituximab-Cytarabine for transplant-eligible patients with mantle cell lymphoma.

    PubMed

    Armand, Philippe; Redd, Robert; Bsat, Jad; Mayuram, Sangeetha; Giardino, Angela; Fisher, David C; LaCasce, Ann S; Jacobson, Caron; Davids, Matthew S; Brown, Jennifer R; Weng, Li; Wilkins, Jennifer; Faham, Malek; Freedman, Arnold S; Joyce, Robin; Jacobsen, Eric D

    2016-04-01

    Chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard therapy for transplant-eligible patients with newly diagnosed mantle cell lymphoma (MCL). The achievement of complete remission (CR) and minimal residual disease (MRD) negativity are associated with better outcomes. We tested an induction regimen of rituximab/bendamustine followed by rituximab/high-dose cytarabine (RB/RC). This phase 2 study (NCT01661881) enrolled 23 transplant-eligible patients aged 42-69, of whom 70% were MCL international prognostic index low-risk. Patients received three cycles of RB followed by three cycles of RC. The primary endpoint of the trial was the rate of CR after six cycles of therapy, with a rate of 75% considered promising. 96% of patients achieved a CR/unconfirmed CR after treatment, meeting the primary objective. One patient progressed on study, one declined ASCT in CR, and the remaining 21 underwent successful stem cell collection and ASCT. After a median follow-up of 13 months, the progression-free survival rate was 96%. Among 15 MRD-evaluable patients who completed treatment, 93% achieved MRD negativity after RB/RC. In conclusion, RB/RC achieves very high CR and MRD negativity rates in transplant-eligible patients, with a favourable safety profile. RB/RC warrants further comparative studies, and may become a useful alternative to RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-based induction regimens in this patient population. PMID:26729345

  12. Monoclonal antibodies in treatment of multiple sclerosis

    PubMed Central

    Rommer, P S; Dudesek, A; Stüve, O; Zettl, UK

    2014-01-01

    Monoclonal antibodies (mAbs) are used as therapeutics in a number of disciplines in medicine, such as oncology, rheumatology, gastroenterology, dermatology and transplant rejection prevention. Since the introduction and reintroduction of the anti-alpha4-integrin mAb natalizumab in 2004 and 2006, mAbs have gained relevance in the treatment of multiple sclerosis (MS). At present, numerous mAbs have been tested in clinical trials in relapsing–remitting MS, and in progressive forms of MS. One of the agents that might soon be approved for very active forms of relapsing–remitting MS is alemtuzumab, a humanized mAb against CD52. This review provides insights into clinical studies with the mAbs natalizumab, alemtuzumab, daclizumab, rituximab, ocrelizumab and ofatumumab. PMID:24001305

  13. Preserved Activity of CD20-Specific Chimeric Antigen Receptor-Expressing T Cells in the Presence of Rituximab.

    PubMed

    Rufener, Gregory A; Press, Oliver W; Olsen, Philip; Lee, Sang Yun; Jensen, Michael C; Gopal, Ajay K; Pender, Barbara; Budde, Lihua E; Rossow, Jeffrey K; Green, Damian J; Maloney, David G; Riddell, Stanley R; Till, Brian G

    2016-06-01

    CD20 is an attractive immunotherapy target for B-cell non-Hodgkin lymphomas, and adoptive transfer of T cells genetically modified to express a chimeric antigen receptor (CAR) targeting CD20 is a promising strategy. A theoretical limitation is that residual serum rituximab might block CAR binding to CD20 and thereby impede T cell-mediated anti-lymphoma responses. The activity of CD20 CAR-modified T cells in the presence of various concentrations of rituximab was tested in vitro and in vivo CAR-binding sites on CD20(+) tumor cells were blocked by rituximab in a dose-dependent fashion, although at 37°C blockade was incomplete at concentrations up to 200 μg/mL. T cells with CD20 CARs also exhibited modest dose-dependent reductions in cytokine secretion and cytotoxicity, but not proliferation, against lymphoma cell lines. At rituximab concentrations of 100 μg/mL, CAR T cells retained ≥50% of baseline activity against targets with high CD20 expression, but were more strongly inhibited when target cells expressed low CD20. In a murine xenograft model using a rituximab-refractory lymphoma cell line, rituximab did not impair CAR T-cell activity, and tumors were eradicated in >85% of mice. Clinical residual rituximab serum concentrations were measured in 103 lymphoma patients after rituximab therapy, with the median level found to be only 38 μg/mL (interquartile range, 19-72 μg/mL). Thus, despite modest functional impairment in vitro, the in vivo activity of CD20-targeted CAR T cells remains intact at clinically relevant levels of rituximab, making use of these T cells clinically feasible. Cancer Immunol Res; 4(6); 509-19. ©2016 AACRSee related Spotlight by Sadelain, p. 473. PMID:27197068

  14. Occurrence of lymphoplasmacytic lymphoma 6 years after amelioration of primary cold agglutinin disease by rituximab therapy.

    PubMed

    Tanaka, Hiroaki; Hashimoto, Shinichiro; Sugita, Yasumasa; Sakai, Shio; Takeda, Yusuke; Abe, Daijiro; Takagi, Toshiyuki; Nakaseko, Chiaki

    2012-10-01

    Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, classified into primary and secondary types. Secondary CAD accompanies infection or malignant disease, most often lymphoma, whereas primary CAD frequently represents a lymphoproliferative bone marrow disorder characterized by clonal expansion of B cells. Here, I describe a case of lymphoplasmacytic lymphoma (LPL) developed 6 years after amelioration of primary CAD by rituximab monotherapy. A 54-year-old Japanese woman was diagnosed with primary CAD characterized by a small fraction of B lymphocytes and kappa laterality in the peripheral blood. M-protein was not detected by immuno-electrophoresis. The patient achieved remission following two courses of rituximab monotherapy. The level of IgM was specifically decreased, although levels of IgG and IgA were slightly increased. Six years after rituximab monotherapy, she developed LPL without CAD recurrence. Flow cytometry performed on bone marrow specimens revealed that lymphoma cells were positive for CD19 and CD20 with kappa laterality. The lymphoma may have transformed from clonal B lymphocytes at presentation of CAD. Rituximab monotherapy induced remission of CAD by specific decrease of IgM level, but did not eliminate the clonal B lymphocytes that may have progressed to LPL. This experience may provide clues toward the understanding of the pathophysiology of primary CAD with clonal lymphoproliferative disease of the bone marrow. PMID:22878940

  15. Use of rituximab as a treatment for systemic lupus erythematosus: retrospective review

    PubMed Central

    Machado, Roberta Ismael Lacerda; Scheinberg, Morton Aaron; de Queiroz, Maria Yvone Carlos Formiga; de Brito, Danielle Christinne Soares Egypto; Guimarães, Maria Fernanda Brandao de Resende; Giovelli, Raquel Altoé; Freire, Eutilia Andrade Medeiros

    2014-01-01

    ABSTRACT Objective: To report the experience in three Brazilian institutions with the use of rituximab in patients with different clinical forms of lupus erythematosus systemic in activity. Methods: The study consisted of a sample of 17 patients with LES, who were already being treated, but that at some stage of the disease showed refractory symptoms. The patients were subdivided into groups according to the clinical manifestation, and the responses for the use of rituximab were rated as complete, partial or no response. Data were collected through a spreadsheet, and used specific parameters for each group. The treatment was carried on by using therapeutic dose of 1g, and repeating the infusion within an interval of 15 days. Results: The clinical responses to rituximab of the group only hematological and of the group only osteoarticular were complete in all cases. In the renal group there was a clinical complete response, two partial and one absent. In the renal and hematological group complete response, there was one death and a missing response. The pulmonary group presented a complete response and two partial. Conclusion: The present study demonstrated that rituximab can bring benefits to patients with lupus erythematosus systemic, with good tolerability and mild side effects; it presented, however, variable response according to the system affected. PMID:24728244

  16. Rituximab is an effective and safe treatment of relapse in elderly patients with resistant warm AIHA.

    PubMed

    Laribi, Kamel; Bolle, Delphine; Ghnaya, Habib; Sandu, Andrea; Besançon, Anne; Denizon, Nathalie; Truong, Catherine; Pineau-Vincent, Fabienne; de Materre, Alix Baugier

    2016-04-01

    We evaluated the efficacy and safety of rituximab for the treatment of 23 elderly patients (median age 78 years) with warm autoimmune haemolytic anaemia (AIHA). The median follow-up was 31 months. Patients had received one to five previous treatments. Rituximab was administered by intravenous infusion at a dose of 375 mg/m(2) once weekly for 4 weeks. The OR rate was 86.9 % (CR = 39.1 %, PR = 47.8 %). Median OS was 87 months. The median OS of patients who reached CR could not be calculated, and that of patients with PR was 67 months. At last follow-up, eight of the 20 responding patients, including one patient in CR and seven in PR, had relapsed after a median of 6 months. Failure to achieve CR was a risk factor for relapse (p = 0.028). We did not identify any pretreatment characteristics predictive of response to rituximab. In conclusion, rituximab is an effective treatment for elderly patients with refractory warm AIHA. PMID:26858026

  17. Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica

    PubMed Central

    Yang, Chun-Sheng; Yang, Li; Li, Ting; Zhang, Da-Qi; Jin, Wei-Na; Li, Min-Shu; Su, Ning; Zhangning, Nannan; Liu, Qiang; Shao, Zong-Hong; Yu, Chunshui

    2013-01-01

    Objective: To determine the effect of a lower dose of rituximab in depleting B lymphocytes, maintaining low B-cell counts, and relapse in patients with neuromyelitis optica (NMO) and NMO spectrum disorders. Methods: We treated 5 Chinese patients with deteriorating NMO and NMO spectrum disorders with a 100-mg IV infusion of rituximab once a week for 3 consecutive weeks, followed by additional infusion of the same dosage depending on circulating B-cell repopulation. Results: This reduced dosage of rituximab was sufficient to deplete B cells and maintain low B-cell counts. None of the treated patients experienced relapse, and all patients exhibited stabilized or improved neurologic function during the 1-year follow-up period. MRI revealed the absence of new lesions, no enhancement in spinal cord and brain, a significant shrinkage of spinal cord segments, and a reduction/disappearance of previous brain lesions. Conclusion: A lower dosage of rituximab may be sufficient in depleting B cells, maintaining low B-cell counts, and preventing disease progression in Chinese patients with NMO. PMID:23884041

  18. Treatment of myelitis in Behçet's disease with rituximab

    PubMed Central

    Messina, Maria Josè; Rodegher, Mariaemma; Scotti, Roberta; Martinelli, Vittorio

    2014-01-01

    Behçet's disease (BD) is a chronic inflammatory disorder that involves the parenchymal central nervous system (neuro-BD, NBD) approximately in 5–49% of patients, causing lesions rarely located in the spinal cord (SC). We report the first case of NBD-myelitis treated with intravenous rituximab. A 41-year-old man affected by BD presented with mild paraparesis with a miliary involvement and a ‘net-like’ gadolinium enhancement (Gde) of the SC. After a therapeutic attempt with pulsed cyclophosphamide and intravenous methylprednisolone, the clinical and neuroradiological course worsened. A progressive improvement was observed after rituximab administration associated with low doses of oral prednisone. No disease activity was detected and the patient reported no adverse event. After six rituximab cycles, cervical MRI was normal while thoracic MRI showed a slight T2–weighted hyperintensity of D4–D10 spinal tract without Gde. A combined use of rituximab and oral steroids resulted in a long-term suppression of NBD activity without any safety concern. PMID:24879733

  19. Burkitt Lymphoma Preceded by Autoimmune Hemolytic Anemia due to Anti-D Antibody.

    PubMed

    Mizuno, Yoshimi; Shimura, Yuji; Horiike, Shigeo; Takimoto, Tomoko; Maegawa, Saori; Tanba, Kazuna; Matsumura-Kimoto, Yayoi; Sumida, Yukari; Tatekawa, Shotaro; Tsukamoto, Taku; Chinen, Yoshiaki; Mizutani, Shinsuke; Nagoshi, Hisao; Yamamoto-Sugitani, Mio; Matsumoto, Yosuke; Kobayashi, Tsutomu; Kuroda, Junya; Taniwaki, Masafumi

    2016-01-01

    We herein report a rare case of Burkitt lymphoma (BL) preceded by autoimmune hemolytic anemia (AIHA) caused by autoantibodies against D antigen. After a partial response to AIHA with prednisolone (PSL) treatment for 7 months, the patient developed BL with a t(8;22)(q24;q11.2) chromosomal translocation. Intensive immunochemotherapy, including rituximab, led to a complete response (CR) of BL; however, anti-D antibody remained detectable in the plasma and antibody-dissociated solution from erythrocytes, thus continuous therapy with PSL was necessary even after achievement of the CR. BL with AIHA is extremely rare, with only one previously reported case in the literature. PMID:27523004

  20. Antithyroid microsomal antibody

    MedlinePlus

    Thyroid antimicrosomal antibody; Antimicrosomal antibody; Microsomal antibody; Thyroid peroxidase antibody; TPOAb ... test is done to confirm the cause of thyroid problems, including Hashimoto thyroiditis . The test is also ...

  1. Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts

    PubMed Central

    Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

    2016-01-01

    Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β−-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β−- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β−-particle RIT for the management of intraperitoneal disease. PMID:27196891

  2. Anti-CD45 Radioimmunotherapy with 90Y but Not 177Lu Is Effective Treatment in a Syngeneic Murine Leukemia Model

    PubMed Central

    Orozco, Johnnie J.; Balkin, Ethan R.; Gooley, Ted A.; Kenoyer, Aimee; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Hylarides, Mark D.; Shadman, Mazyar; Green, Damian J.; Gopal, Ajay K.; Press, Oliver W.; Pagel, John M.

    2014-01-01

    Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD45 Ab conjugates (DOTA-30F11) targeted hematologic tissues, as at 24 hours 48.8±21.2 and 156±14.6% injected dose per gram of tissue (% ID/g) of 90Y-DOTA-30F11 and 54.2±9.5 and 199±11.7% ID/g of 177Lu-DOTA-30F11 accumulated in bone marrow (BM) and spleen, respectively. However, 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi 90Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi 90Y-DOTA-30F11 had a median survival 66 days. 90Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, 90Y was more effective than 177Lu for anti-CD45 RIT of AML in this murine leukemia model. PMID:25460570

  3. Anti-CD45 Pretargeted Radioimmunotherapy using Bismuth-213: High Rates of Complete Remission and Long-Term Survival in a Mouse Myeloid Leukemia Xenograft Model

    SciTech Connect

    Pagel, John M; Kenoyer, Aimee L; Back, Tom; Hamlin, Donald K; Wilbur, D Scott; Fisher, Darrell R; Park, Steven I; Frayo, Shani; Axtman, Amanda; Orgun, Nural; Orozoco, Johnnie; Shenoi, Jaideep; Lin, Yukang; Gopal, Ajay K; Green, Damian J; Appelbaum, Frederick R; Press, Oliver W

    2011-07-21

    Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and DOTA-biotin labeled with β-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. α-emitting radionuclides exhibit high cytotoxicity coupled with a short path-length, potentially increasing the therapeutic index and making them an attractive alternative to β-emitting radionuclides for patients with Acute Myeloid Leukemia (AML). Accordingly, we have used 213Bi in mice with human leukemia xenografts. Results demonstrated excellent localization of 213Bi-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5 ± 1.1% of the injected dose of 213Bi was delivered per gram of tumor. α imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after 213Bi-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a β-emitting radionuclide (90Y) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of 213Bi-DOTA-biotin given 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of 213Bi- or 90Y-DOTA-biotin, 80% and 20%, respectively, survived leukemia-free for >100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an α-emitting radionuclide may be highly effective and minimally toxic for treatment of AML.

  4. Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from (177)Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts.

    PubMed

    Yong, Kwon Joong; Milenic, Diane E; Baidoo, Kwamena E; Brechbiel, Martin W

    2016-01-01

    Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β(-)-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes (177)Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with (177)Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with (177)Lu-trastuzumab comparatively to animals treated with a non-specific control, (177)Lu-HuIgG, and then to prior published results obtained using (212)Pb-trastuzumab, an α-particle RIT agent. (177)Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein (212)Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. (177)Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β(-)- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β(-)-particle RIT for the management of intraperitoneal disease. PMID:27196891

  5. Therapeutic efficacy of 177Lu-CHX-A″-DTPA-hu3S193 radioimmunotherapy in prostate cancer is enhanced by EGFR inhibition or docetaxel chemotherapy

    PubMed Central

    Kelly, Marcus P; Lee, Sze Ting; Lee, F-T; Smyth, Fiona E; Davis, Ian D.; Brechbiel, Martin W; Scott, Andrew M

    2008-01-01

    Background This study investigated the biodistribution and therapeutic efficacy of Lutetium-177 (177Lu) radiolabeled anti-Lewis Y monoclonal antibody hu3S193 radioimmunotherapy (RIT) in mice bearing prostate cancer xenografts. The ability of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor AG1478 and docetaxel chemotherapy to enhance the efficacy of RIT was also assessed in vivo. Methods The in vitro cytotoxicity of 177Lu labeled hu3S193 on Ley positive DU145 prostate cancer cells was assessed using proliferation assays, with induction of apoptosis measured by ELISA. The in vivo biodistribution and tumor localization of 177Lu-hu3S193 was assessed in mice bearing established DU145 tumor xenografts. The efficacy and maximum tolerated dose of 177Lu-hu3S193 RIT in vivo was determined by a dose escalation study. EGFR inhibitor AG1478 or docetaxel chemotherapy was administered at sub-therapeutic doses in conjunction with RIT in vivo. Results 177Lu-hu3S193 mediated significant induction of cytotoxicity and apoptosis in vitro. In vivo analysis of 177Lu-hu3S193 biodistribution demonstrated specific targeting of DU145 prostate cancer xenografts, with maximal tumor uptake of 33.2 ± 3.9 %ID/g observed at 120 hr post injection. In RIT studies, 177Lu-hu3S193 caused specific and dose-dependent inhibition of prostate cancer tumor growth. A maximum tolerated dose of 350μCi was determined for 177Lu-hu3S193. Combination of 177Lu-hu3S193 RIT with EGFR inhibitor AG1478 or docetaxel chemotherapy both significantly improved efficacy. Conclusions 177Lu-hu3S193 RIT is effective as a single agent in the treatment of Ley positive prostate cancer models. The enhancement of RIT by AG1478 or docetaxel indicates the promise of combined modality strategies. PMID:18942092

  6. Rituximab in refractory myasthenia gravis: a prospective, open-label study with long-term follow-up.

    PubMed

    Anderson, Dustin; Phan, Cecile; Johnston, Wendy S; Siddiqi, Zaeem A

    2016-07-01

    We examined the clinical effectiveness of rituximab in fourteen patients with refractory myasthenia gravis (MG). Manual muscle testing (MMT) score was recorded at baseline and followed during the course of the study. Steroid dose, frequency of intravenous immunoglobulin (IVIG) infusions, and plasma exchange (PLEX) were also monitored throughout the duration of the study. All patients responded dramatically to rituximab, as measured by a change in MMT score, prednisone dose, or the frequency of IVIG infusions or PLEX. Rituximab appears safe and effective for the treatment of refractory MG. It should be considered as a therapeutic option in refractory patients. PMID:27386504

  7. Barriers to the Access and Use of Rituximab in Patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: A Physician Survey.

    PubMed

    Baer Ii, William H; Maini, Archana; Jacobs, Ira

    2014-01-01

    Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia. PMID:24810947

  8. Quality Control of Therapeutic Monoclonal Antibodies at the Hospital After Their Compounding and Before Their Administration to Patients.

    PubMed

    Jaccoulet, Emmanuel; Smadja, Claire; Taverna, Myriam

    2016-01-01

    Monoclonal antibodies (mAbs) are widely used in cancer therapy and recently many new mAbs have gained EMA and FDA approvals for oncology indications. Here we describe a highly reproducible CZE method, relying on a cationic coating allowing separation and identification of a complex mixture of four compounded mAbs widely used in cancer therapy (cetuximab, rituximab, bevacizumab, and trastuzumab). PMID:27473490

  9. Rituximab Effectiveness and Safety for Treating Primary Sjögren’s Syndrome (pSS): Systematic Review and Meta-Analysis

    PubMed Central

    Souza, Francine Bertolais do Valle; Porfírio, Gustavo José Martiniano; Andriolo, Brenda Nazaré Gomes; de Albuquerque, Julia Vajda; Trevisani, Virginia Fernandes Moça

    2016-01-01

    Background Primary Sjögren’s Syndrome (pSS) is a systemic autoimmune disease that involves the exocrine glands and internal organs. pSS leads to destruction and loss of secretory function due to intense lymphoplasmacytic infiltration. Therapeutic options include mainly symptomatic and supportive measures, and traditional immunosuppressant drugs have shown no effectiveness in randomized trials. Rituximab (RTX) is a chimeric antibody anti-CD20 that leads to B cell depletion by diverse mechanisms. There is evidence that this drug may be effective for treating pSS. The objective of this systematic review was to evaluate Rituximab effectiveness and safety for treating pSS. Methods and Findings We conducted a systematic review of RCTs published until December 2015, with no language restriction. We registered a protocol on Plataforma Brasil (40654814.6.0000.5505) and developed search strategies for the following scientific databases: MEDLINE, EMBASE, CENTRAL and LILACS. We included adults with established pSS diagnosis and considered the use of Rituximab as intervention and the use of other drugs or placebo as control. Four studies met our eligibility criteria: three with low risk of bias and one with uncertain risk of bias. The total number of participants was 276 (145 RTX, 131 placebo). We assessed the risk of bias of each included study and evaluated the following as primary outcomes: lacrimal gland function, salivary gland function, fatigue improvement and adverse events. We found no significant differences between the groups in the Schirmer test at week 24 meta-analysis (MD 3.59, 95% CI -2.89 to 10.07). Only one study evaluated the lissamine green test and reported a statistically significant difference between the groups at week 24 (MD -2.00, 95% CI -3.52 to -0.48). There was a significant difference between the groups regarding salivary flow rate (MD 0.09, 95% CI 0.02 to 0.16) and improvement in fatigue VAS at weeks 6 (RR 3.98, 95% CI 1.61 to 9.82) and week 16

  10. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words.

    PubMed

    Mirick, G R; Bradt, B M; Denardo, S J; Denardo, G L

    2004-12-01

    The United States Food and Drug Administration (FDA) has approved unconjugated monoclonal antibodies (MAbs) for immunotherapy (IT) of B-cell lymphoma, breast cancer and acute myeloid leukemia. More recently, approval has been given for conjugated ZevalinTM ((90)yttrium ibritumomab tiuxetan, IDEC-Y2B8, Biogen Idec, Cambridge, MA) and BexxarTM ((131)I-tositumomab, Corixa, Corp., Seattle, WA and GlaxoSmithKline, Philadelphia, PA) anti-CD20 MAbs for use in radioimmunotherapy (RIT) of non-Hodgkin's lymphoma (NHL), thus redefining the standard care of cancer patients. Because of, and despite a lack of basis for concern about allergic reactions due to human antibody responses to these foreign proteins, assays were developed to determine HAGA (human anti-globulin antibody) levels that developed in patient sera following treatment with MAbs. Strategies were also devised to ''humanize'' MAbs and to temporarily block patient immune function with drugs in order to decrease the seroconversion rates, with considerable success. On the other hand, a survival advantage has been observed in some patients who developed a HAGA following treatment. This correlates with development of an anti-idiotype antibody cascade directed toward the MAbs used to treat these patients. What follows is a selective review of HAGA and its effect on cancer treatment over the past 2 decades. PMID:15640788

  11. A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma.

    PubMed

    Coiffier, Bertrand; Thieblemont, Catherine; de Guibert, Sophie; Dupuis, Jehan; Ribrag, Vincent; Bouabdallah, Réda; Morschhauser, Franck; Navarro, Robert; Le Gouill, Steven; Haioun, Corinne; Houot, Roch; Casasnovas, Olivier; Holte, Harald; Lamy, Thierry; Broussais, Florence; Payrard, Sandrine; Hatteville, Laurence; Tilly, Hervé

    2016-06-01

    In this phase II, multicentre, single-arm study, 52 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) received the anti-CD19 antibody-drug conjugate coltuximab ravtansine (55 mg/m(2) ) and rituximab (375 mg/m(2) ) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0-41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2-78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0-72·1%]) or first-line therapy (15·4% [80% CI: 6·9-28·4%]). Median progression-free survival, overall survival and duration of response were 3·9 [80% CI: 3·22-3·98], 9·0 [80% CI: 6·47-13·67] and 8·6 (range: 0-18) months, respectively. The pharmacokinetics of both drugs were unaffected by co-administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL. PMID:27010483

  12. Rapid Reduction in Donor-Specific Anti-Human Leukocyte Antigen Antibodies and Reversal of Antibody-Mediated Rejection With Bortezomib in Pediatric Heart Transplant Patients

    PubMed Central

    Morrow, William Robert; Frazier, Elizabeth A.; Mahle, William T.; Harville, Terry O.; Pye, Sherry E.; Knecht, Kenneth R.; Howard, Emily L.; Smith, R. Neal; Saylors, Robert L.; Garcia, Xiomara; Jaquiss, Robert D.B.; Woodle, E. Steve

    2013-01-01

    Background High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce antihuman leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. Methods Patients received four intravenous dose of bortezomib (1.3 mg/m2) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. Results AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. Conclusions Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA. PMID:22179403

  13. Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (Head and neck cancer: ImmunoChemo and Radiotherapy with Erbitux) – a multicenter phase IV trial

    PubMed Central

    2013-01-01

    Background In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before. Methods/design The HICARE study is a national, multicenter, prospective phase IV study exploring the different types of skin reactions that occur in patients with LASCCHN undergoing radioimmun(chemo)therapy with the EGFR inhibitor cetuximab. 500 patients with LASCCHN will be enrolled in 40 participating sites in Germany. Primary endpoint is the rate of radiation dermatitis NCI CTCAE grade 3 and 4 (v. 4.02). Radioimmunotherapy will be applied according to SmPC, i.e. cetuximab will be administered as loading dose and then weekly during the radiotherapy. Irradiation will be applied as intensity-modulated radiation therapy (IMRT) or 3D-dimensional radiation therapy. Discussion The HICARE trial is expected to be one of the largest trials ever conducted in head and neck cancer patients. The goal of the HICARE trial is to differentiate skin reactions caused by radiation from those caused by the monoclonal antibody cetuximab, to evaluate the incidence and severity of these skin reactions and to correlate them with outcome parameters. Besides, the translational research program will

  14. Safety and efficacy of rituximab treatment for vasculitis in hepatitis B virus-associated type II cryoglobulinemia: a case report

    PubMed Central

    2012-01-01

    Introduction Systemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins have already been achieved using rituximab in hepatitis C virus-positive immunocompetent patients. Conversely, to the best of our knowledge there are no reports in the literature regarding the use of rituximab in hepatitis B virus-associated cryoglobulinemia. Case presentation We report here the case of a 60-year-old Caucasian man who presented with hepatitis B virus-associated type II cryoglobulinemia with severe multisystem disease, including membranoproliferative glomerulonephritis with acute renal failure. The vasculitis was refractory to conventional and antiviral therapy but rituximab use led to a fall in cryoglobulin levels and disease control. The B-cell depletion was safe and efficient to induce a complete remission of the disease. Conclusion Our case highlights the benefit and the efficacy of rituximab in association with antiviral therapy in small vessel vasculitis related to hepatitis B virus-associated mixed cryoglobulinemia. PMID:22284897

  15. Radiation dosimetry results from a Phase II trial of ibritumomab tiuxetan (Zevalin) radioimmunotherapy for patients with non-Hodgkin's lymphoma and mild thrombocytopenia.

    PubMed

    Wiseman, Gregory A; Leigh, Bryan R; Erwin, William D; Sparks, Richard B; Podoloff, Donald A; Schilder, Russell J; Bartlett, Nancy L; Spies, Stewart M; Grillo-López, Antonio J; Witzig, Thomas E; White, Christine A

    2003-04-01

    This was a 30-patient Phase II trial of reduced-dose (90)Y ibritumomab tiuxetan (Zevalin) RIT for patients with low-grade, follicular, or transformed B-cell NHL and mild thrombocytopenia. Patients were given an imaging dose of (111)In-labeled ibritumomab tiuxetan for dosimetry measurements. One week later, patients were administered a therapeutic dose of 0.3 mCi/kg (11 MBq/kg) (90)Y ibritumomab tiuxetan. Both (111)In- and (90)Y-labeled ibritumomab tiuxetan doses were preceded by an infusion of 250 mg/m(2) rituximab (Rituxan, MabThera) an unlabeled chimeric anti-CD20 antibody, to clear peripheral blood B cells and improve biodistribution of the radiolabeled antibody. For all 30 patients, normal organ and red marrow radiation absorbed doses were well below protocol-defined limits of 2000 cGy and 300 cGy, respectively. Median radiation absorbed doses were 48 cGy to red marrow (range: 6.5-95 cGy), 393 cGy to liver (range: 92-1581 cGy), 522 cGy to spleen (range: 165-1711 cGy), 162 cGy to lungs (41-295 cGy), and 14 cGy to kidneys (0.03-65 cGy). Though most correlative analyses were negative, certain analyses demonstrated a statistically significant correlation between the severity or duration of thrombocytopenia and pharmacokinetic or dosimetric parameters. These correlations were not consistent across the total patient population, and therefore, could not be exploited to predict hematologic toxicity. PMID:12804042

  16. Effect of different cell cluster models on the radiobiological output for (211)At-radioimmunotherapy.

    PubMed

    Lin, Hui; Jing, Jia; Xu, Yuanying

    2011-02-01

    The cell cluster modeling is a widely used method to estimate the small-scale dosimetry and provides the implication for a clinic. This work evaluated the effect of different regular cluster models on the radiobiological outputs for (211)At-radioimmunotherapy. The cell activity threshold was estimated using a tumor control probability of 0.90. Basically, regular models show similar features with cluster configuration and cell dimension variation. However, their individual results such as the cumulated activity threshold per cell and the prescription dose per volume should not be substituted reciprocally. The tissue composed of smaller cells or midcell packing will need a little more high prescription dose per volume. The radiation sensitivity parameters in a linear-quadratic model are critical to decide the radiobiological response with dose. The cumulated cell activity threshold increases exponentially with α decreasing, and its influence on the big cell dimension is more than on the small one. The different subsources affect radioresistant organs or tissues more remarkably than radiosensitive ones, especially the cells with large cytoplasm. The heterogeneous activity of Gaussian distribution will decrease the therapeutical effectiveness for the nucleus source, but its influence on the cytoplasm and cell surface sources is a little uncertain, as their real mean value is always higher than its set mean value by assuming the cell activity uptakes from zero. Careful usage of underdose with heterogeneous activity distribution should be practiced in clinics. The deteriorated heterogeneous distribution will salvage the potential subversive and lead to the failure of tumor local control. Some cells with no or little activity that are located on the edge or vertex of cube or corner models will have the ability to survive, as there is a lack of a part of the cross-fire dose effect, and so more attention should be paid in selecting the dosage. Although this work focuses on

  17. Improved radioimmunotherapy of hematologic malignancies. Progress report, November 1, 1993--October 31, 1994

    SciTech Connect

    Press, O.W.

    1994-08-04

    This report summaries progress made during the time interval between November 1, 1993 and October 31, 1994 and briefly describes studies on the metabolism of antibodies targeting B cell antigens, retention of labeled antibodies by human B cell lymphocytes, and tissue distribution of Chloramine T and tyramine cellobiose labeled antibodies in mice harboring a human erythroleukemia tumor transplant.

  18. Antithyroglobulin antibody

    MedlinePlus

    ... may be due to: Graves disease Hashimoto thyroiditis Hypothyroidism Systemic lupus erythematosus (SLE) Thyrotoxicosis Type 1 diabetes ... Antibody Chronic thyroiditis (Hashimoto disease) Graves disease Hyperthyroidism Hypothyroidism Systemic lupus erythematosus T3 test Update Date 5/ ...

  19. Rituximab off label use for difficult-to-treat auto-immune diseases: reappraisal of benefits and risks.

    PubMed

    Sailler, Laurent

    2008-02-01

    Rituximab is increasingly used off label for difficult-to-treat auto-immune diseases. We reviewed the main case series or clinical studies to identify the best indications of rituximab and the situations at substantial risks for adverse events. Refractory immune thrombocytopenic purpura was the main indication. However, the long term benefit-to-risk ratio of rituximab treatment before or after splenectomy is unknown. A single 375 mg/m2 infusion may be as efficacious as the classical four infusions cycle. Rituximab is the best treatment for cold agglutinin disease. In warm agglutinin auto-immune anaemia, its efficacy has essentially been reported in chronic lymphocytic leukemia (CLL) patients and in children. In CLL patients, lethal adverse events occurred in patients also receiving cyclophosphamide. Rituximab seems to have an interesting benefit-to-risk ratio in Wegener granulomatosis (excepted in granulomatous lesions), HCV-associated symptomatic cryoglobulinemia in patients unresponsive to anti-viral therapy, pemphigus and thrombotic thrombocytopenic purpura. Efficacy and safety data in lupus are difficult to interpret. Serum sickness disease is not exceptional in immune thrombocytopenic purpura (ITP), lupus and sicca syndrome patients. A substantial infectious risk has been reported in pemphigus patients and in post-renal transplant cryoglobulinemia. Double-blind randomised controlled trials and phase IV studies are mandatory in most clinical settings to confirm the overall favourable perception of rituximab benefit to risk ratio. PMID:18270863

  20. A Randomized Controlled Trial of Rituximab Following Failure of Antiviral Therapy for Hepatitis C-Associated Cryoglobulinemic Vasculitis

    PubMed Central

    Sneller, Michael C.; Hu, Zonghui; Langford, Carol A.

    2011-01-01

    OBJECTIVES To report on the results of a randomized controlled trial of rituximab in hepatitis C virus (HCV)-associated mixed cryoglobulinemic vasculitis. METHODS We conducted an open-label single center randomized controlled trial of rituximab (375 mg/m2 per week for 4 weeks) compared to best available therapy for treatment of patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy failed to induce remission. The primary endpoint was remission at 6 months from study entry. RESULTS A total of 24 patients were enrolled. Baseline disease activity and organ involvement were similar in the two groups. Ten patients in the rituximab group (83%) were in remission at study month 6, compared with 1 patient in the control group (8%), a result that met criterion for stopping the study (P<0.001). The median duration of remission for rituximab-treated patients reaching the primary endpoint was 7 months. No adverse effect of rituximab on HCV plasma viremia or hepatic transaminase levels was observed. CONCLUSIONS Therapy with rituximab was well tolerated and effective treatment for patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy fails to induce remission. PMID:22147444

  1. Imaging and measuring the rituximab-induced changes of mechanical properties in B-lymphoma cells using atomic force microscopy

    SciTech Connect

    Li, Mi; Liu, Lianqing; Xi, Ning; Wang, Yuechao; Dong, Zaili; Tabata, Osamu; Xiao, Xiubin; Zhang, Weijing

    2011-01-14

    Research highlights: {yields} Single B-lymphoma living cells were imaged by AFM with the assistance of microfabricated pillars. {yields} The apoptosis of B-lymphoma cells triggered by rituximab without cross-linking was observed by AO/EB double fluorescent staining. {yields} The B-lymphoma cells became dramatically softer after adding rituximab. -- Abstract: The topography and mechanical properties of single B-lymphoma cells have been investigated by atomic force microscopy (AFM). With the assistance of microfabricated patterned pillars, the surface topography and ultrastructure of single living B-lymphoma cell were visualized by AFM. The apoptosis of B-lymphoma cells induced by rituximab alone was observed by acridine orange/ethidium bromide (AO/EB) double fluorescent staining. The rituximab-induced changes of mechanical properties in B-lymphoma cells were measured dynamically and the results showed that B-lymphoma cells became dramatically softer after incubation with rituximab. These results can improve our understanding of rituximab'effect and will facilitate the further investigation of the underlying mechanisms.

  2. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE))

    PubMed Central

    Emery, P; Deodhar, A; Rigby, W F; Isaacs, J D; Combe, B; Racewicz, A J; Latinis, K; Abud-Mendoza, C; Szczepański, L J; Roschmann, R A; Chen, A; Armstrong, G K; Douglass, W; Tyrrell, H

    2010-01-01

    Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment. Methods Patients with active disease on stable MTX (10–25 mg/week) were randomised to rituximab 2×500 mg (n=168), rituximab 2×1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) ≥2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2×500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. Results At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2×500 mg) + MTX, rituximab (2×1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48. Conclusions Rituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses. PMID:20488885

  3. The development of potential antibody-based therapies for myeloma

    PubMed Central

    Sherbenou, Daniel W.; Behrens, Christopher R.; Su, Yang; Wolf, Jeffrey L.; Martin, Thomas G.; Liu, Bin

    2015-01-01

    With optimal target antigen selection antibody-based therapeutics can be very effective agents for hematologic malignancies, but none have yet been approved for myeloma. Rituximab and brentuximab vedotin are examples of success for the naked antibody and antibody–drug conjugate classes, respectively. Plasma cell myeloma is an attractive disease for antibody-based targeting due to target cell accessibility and the complementary mechanism of action with approved therapies. Initial antibodies tested in myeloma were disappointing. However, recent results from targeting well-characterized antigens have been more encouraging. In particular, the CD38 and CD138 targeted therapies are showing single-agent activity in early phase clinical trials. Here we will review the development pipeline for naked antibodies and antibody–drug conjugates for myeloma. There is clear clinical need for new treatments, as myeloma inevitably becomes refractory to standard agents. The full impact is yet to be established, but we are optimistic that the first FDA-approved antibody therapeutic(s) for this disease will emerge in the near future. PMID:25294123

  4. Radioimmunotherapy of non-Hodgkin's lymphoma: clinical development of the Zevalin regimen.

    PubMed

    Theuer, Charles P; Leigh, Bryan R; Multani, Pratik S; Allen, Roberta S; Liang, Bertrand C

    2004-01-01

    Zevalin (ibritumomab tiuxetan; IDEC Pharmaceuticals Corporation, San Diego, CA, USA) was approved by the United States Food and Drug Administration on February 19, 2002, following 9 years of clinical development. Six clinical studies supported the Zevalin Biologics License Application. The Zevalin regimen is indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), and for those with follicular NHL refractory to Rituxan (rituximab, MabThera; IDEC Pharmaceuticals Corporation, San Diego, CA and Genentech, South San Francisco, CA). In the year following FDA approval, approximately 1300 patients were treated in clinical trials or with the commercially available product. PMID:15504711

  5. Adverse Events of Monoclonal Antibodies Used for Cancer Therapy

    PubMed Central

    Guan, Mei; Zhou, Yan-Ping; Sun, Jin-Lu; Chen, Shu-Chang

    2015-01-01

    In 1997, the first monoclonal antibody (MoAb), the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug administration for use in cancer patients. Since then, the panel of MoAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has continued to expand, currently encompassing a stunning amount of 20 distinct molecules for 11 targets. We provide a brief scientific background on the use of MoAbs in cancer therapy, review all types of monoclonal antibodies-related adverse events (e.g., allergy, immune-related adverse events, cardiovascular adverse events, and pulmonary adverse events), and discuss the mechanism and treatment of adverse events. PMID:26075239

  6. Adverse events of monoclonal antibodies used for cancer therapy.

    PubMed

    Guan, Mei; Zhou, Yan-Ping; Sun, Jin-Lu; Chen, Shu-Chang

    2015-01-01

    In 1997, the first monoclonal antibody (MoAb), the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug administration for use in cancer patients. Since then, the panel of MoAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has continued to expand, currently encompassing a stunning amount of 20 distinct molecules for 11 targets. We provide a brief scientific background on the use of MoAbs in cancer therapy, review all types of monoclonal antibodies-related adverse events (e.g., allergy, immune-related adverse events, cardiovascular adverse events, and pulmonary adverse events), and discuss the mechanism and treatment of adverse events. PMID:26075239

  7. Synthesis of a new bifunctional chelating agent for radioimmunotherapy: Cyclohexyl fused tetraazacyclodo-decanetetraacetic acid

    SciTech Connect

    Sweet, M.P.; Mease, R.C.; Lambert, C.; Srivastava, S.C.

    1996-05-01

    Preorganization of the coordinating groups within a chelating agent increases the stability of its metal-ligand complexes. For example, 1,2-diaminocyclo-hexanetetraacetic acid (CDTA) forms metal complexes with stability constants 1-3 orders of magnitude higher than the corresponding complexes of EDTA. Incorporation of a cyclohexyl group into a macrocyclic ligand produces a similar effect; stability constants of Cu complexes of tetrathiocyclotetradecanes are increased by 1.5 orders of magnitude by incorporating one cyclohexyl group into the macrocyclic ring and 3 orders of magnitude by incorporating two cyclohexyl moieties. In this study, we have synthesized cycohexyl DOTA (C-DOTA) in which the cyclohexyl group is fused to two carbons of the macrocyclic ring. Alkylation of disodium ethylene ditosylamide with trans-1,2-di(bromoacetamido)cyclohexane afforded the C{sub 8}N{sub 4} macrocycle. Reduction with lithium aluminum hydride not only reduced the amide moieties to amines but also removed the tosyl protecting groups affording the cyclohexylcyclen. Cyanomethylation followed by hydrolysis gave C-DOTA in an overall yield of 9.4%. C-DOTA is expected to offer improvements in the biodistribution of radiometal immunoconjugates for radioimmunotherapy, in particular with Sc-47, Y-90, and Sm-153 that have given encouraging results using the plain DOTA ligand.

  8. Evaluation of effects on the peritoneum after intraperitoneal α-radioimmunotherapy with (211)At.

    PubMed

    Cederkrantz, Elin; Angenete, Eva; Bäck, Tom; Falk, Peter; Haraldsson, Börje; Ivarsson, Marie-Louise; Jensen, Holger; Lindegren, Sture; Hultborn, Ragnar; Jacobsson, Lars

    2012-08-01

    The introduction of the short-lived α-emitter (211)At to intraperitoneal radioimmunotherapy has raised the issue of the tolerance dose of the peritoneum. The short range of the α-particles (70 μm) and the short half-life (7.21 h) of the nuclide yield a dose distribution in which the peritoneum is highly irradiated compared with other normal tissues. To address this issue, mice were injected with (211)At-trastuzumab to irradiate the peritoneum to absorbed doses ranging between 0 and 50 Gy and followed for up to 34 weeks. The peritoneum-to-plasma clearance of a small tracer, (51)Cr-ethylenediamine tetraacetic acid, was measured for evaluation of the small solute transport capacity of the peritoneal membrane. The macroscopic status of the peritoneum and the mesenteric windows was documented when the mice were sacrificed. Biopsies of the peritoneum were taken for morphology and immunohistochemical staining against plasminogen activator inhibitor-1 and calprotectin. Peritoneum-to-plasma clearance measurements indicated a dose-dependent decrease in peritoneal transport capacity in irradiated mice. However, macroscopic and microscopic evaluations of the peritoneal membrane showed no difference between irradiated mice versus controls. The results imply that the peritoneal membrane tolerates absorbed doses as high as 30-50 Gy from α-particle irradiation with limited response. PMID:22690847

  9. Apoferritin-Templated Yttrium Phosphate Nanoparticle Conjugates for Radioimmunotherapy of Cancers

    SciTech Connect

    Wu, Hong; Wang, Jun; Wang, Zheming; Fisher, Darrell R.; Lin, Yuehe

    2008-05-01

    We report a templated-synthetic approach based on apoferritin to prepare radionuclide nanoparticle (NP) conjugates. Non-radioactive yttrium (89Y) was used as model target and surrogate for radioyttrium (90Y) to prepare the nanoparticle conjugate. The center cavity and multiple channel structure of apoferritin offer a fast and facile method to precipitate yttrium phosphate by diffusing yttrium and phosphate ions into the cavity of apofrritin, resulting a core-shell nanocomposite. The yttrium phosphate/apoferritin nanoparticle was functionalized with biotin for further application. The synthesized nanoparticle was characterized by transmission electron microscopy (TEM) and x-ray photoelectron spectroscopy (XPS). We found that the resulting nanoparticles were uniform in size, with a diameter of around 8 nm. We tested the pre-targeting capability of the biotin-modified yttrium phosphate/apoferritin nanoparticle (yttrium phosphate/apoferritin nanoparticle) conjugate with streptavidin-modified magnetic beads and with aid of biotin-modified fluorecein isothiocyanate (FITC) tracer. This work shows that an yttrium phosphate NP conjugate provides a fast, simple and efficient method to prepare radioactive yttrium conjugate for applications in radioimmunotherapy of cancer.

  10. Succinylated polylysine as a possible link between an antibody molecule and deferoxamine

    SciTech Connect

    Slinkin, M.A.; Klibanov, A.L.; Khaw, B.A.; Torchilin, V.P. )

    1990-07-01

    Modification of antibodies with chelating polymers may be helpful for radioimmunoimaging, radioimmunotherapy, and NMR tomography. Succinylated polylysine was activated with carbodiimide/N-hydroxysulfosuccinimide in dimethyl sulfoxide and isolated as a dry solid. Sulfosuccinimide-esterified polymer was used for the two-stage coupling of an amino-containing chelating agent (deferoxamine) to monoclonal R11D10 (IgG) or its Fab fragment. Conjugates were separated from free components by using gel-chromatography and anion-exchange chromatography. Antibody-coupling efficiency and the loss of its immunoreactivity upon modification have been studied for polymers with different deferoxamine content. Specific binding of 67Ga to the corresponding antigen via the conjugate has been demonstrated.

  11. Primary renal lymphoma: long-term results of two patients treated with a chemotherapy + rituximab protocol.

    PubMed

    Vázquez-Alonso, F; Puche-Sanz, I; Sánchez-Ramos, C; Flores-Martín, J; Vicente-Prados, J; Cózar-Olmo, J M

    2012-01-01

    Primary renal lymphoma (PRL) is a rare disease of which the etiology and pathogenesis remain controversial, and there is currently no standard treatment for it. We present the results of a long-term followup of two patients who were diagnosed with PRL and treated with cyclophosphamide, adriamycin, vincristine, prednisolone and rituximab (CHOP + R) regimen. Both patients reached a complete response, and there is no evidence of recurrence after 4.5- and 5-year followup periods. Based on our experience and other recently published studies, we recommend the combination of CHOP + rituximab as the elective treatment for this disease. To our knowledge, this is the longest followup period with a complete response that has been reported with this modality of treatment. PMID:22997596

  12. Leuconostoc sp. Meningitis in a Patient Treated with Rituximab for Mantle Cell Lymphoma

    PubMed Central

    Holik, Hrvoje; Coha, Božena; Šiško, Marijan; Tomić-Paradžik, Maja

    2015-01-01

    We present a 64-year-old man who was treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemoimmunotherapy for mantle cell lymphoma and developed purulent meningitis, probably caused by Leuconostoc sp. The patient had severe hypogammaglobulinemia, which is a possible complication of rituximab therapy. To our knowledge and after reviewing the available medical literature, this is the first described case of purulent meningitis caused by Leuconostoc sp. in a patient with mantle cell lymphoma that appeared after treatment with the R-CHOP protocol. The diagnosis of purulent meningitis was based on clinical, laboratory and cytological cerebrospinal fluid findings, in addition to blood culture results in which we isolated Leuconostoc sp. The patient was treated with meropenem with full recovery. PMID:26376594

  13. Rituximab: how approval history is reflected by a corresponding patent filing strategy.

    PubMed

    Storz, Ulrich

    2014-01-01

    Because drug development is not a static process, a drug's market authorisation may change over time. In many cases, the number of indications for which a drug is approved increases. Because this facet of drug development also comes at significant costs, a corresponding patent filing strategy is required to protect these investments. The strategy as applied to rituximab, which is approved for a variety of indications, is discussed in this review. PMID:24866199

  14. High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma

    PubMed Central

    Ambady, Prakash; Abdelaziz, Ahmed; Sarai, Guneet; Bonekamp, David; Blakeley, Jaishri; Grossman, Stuart A.; Ye, Xiaobu

    2014-01-01

    Objective: To evaluate the efficacy of rituximab (R) when added to high-dose methotrexate (HD-MTX) in patients with newly diagnosed immunocompetent primary CNS lymphomas (PCNSLs). Methods: Immunocompetent adults with newly diagnosed PCNSL treated at The Johns Hopkins Hospital between 1995 and 2012 were investigated. From 1995 to 2008, patients received HD-MTX monotherapy (8 g/m2 initially every 2 weeks and after complete response [CR] monthly to complete 12 months of therapy). From 2008 to 2012, patients received the same HD-MTX with rituximab (375 mg/m2) with each HD-MTX treatment. CR rates and median overall and progression-free survival were analyzed for each patient cohort in this single-institution, retrospective study. Results: A total of 81 patients were identified: 54 received HD-MTX (median age 66 years) while 27 received HD-MTX/R (median age 65 years). CR rates were 36% in the HD-MTX cohort and 73% in the HD-MTX/R cohort (p = 0.0145). Median progression-free survival was 4.5 months in the HD-MTX cohort and 26.7 months in the HD-MTX/R cohort (p = 0.003). Median overall survival was 16.3 months in the HD-MTX cohort and has not yet been reached in the HD-MTX/R cohort (p = 0.01). Conclusions: The addition of rituximab to HD-MTX appears to improve CR rates as well as overall and progression-free survival in patients with newly diagnosed PCNSL. Comparisons of long-term survival in the 2 cohorts await further maturation of the data. Classification of evidence: This study provides Class III evidence that in immunocompetent patients with PCNSL, HD-MTX plus rituximab compared with HD-MTX alone improves CR and overall survival rates. PMID:24928128

  15. CD20-Directed Antibody-Mediated Immunotherapy Induces Responses and Facilitates Hematologic Recovery in Patients With Waldenstrom's Macroglobulinemia.

    PubMed

    Treon, Steven P.; Agus, David B.; Link, Brian; Rodrigues, Gilberto; Molina, Arturo; Lacy, Martha Q.; Fisher, David C.; Emmanouilides, Christos; Richards, Arthur I.; Clark, Bruce; Lucas, Marjorie S.; Schlossman, Robert; Schenkein, David; Lin, Boris; Kimby, Eva; Anderson, K. C.; Byrd, John C.

    2001-05-01

    SUMMARY: Waldenstrom's macroglobulinemia (WM, lymphoplasmacytic lymphoma) is a B-cell lymphoproliferative disorder in which CD20 is expressed on tumor cells from most patients. Several small studies have suggested a benefit from the anti-CD20 monoclonal antibody rituximab (Rituxan, MabThera) in patients with WM. In this retrospective study, we examined the outcome of 30 previously unreported patients with WM who received treatment with single-agent rituximab (median age 60; range 32-83 years old). The median number of prior treatments for these patients was 1 (range 0-6), and 14 patients (47%) received a nucleoside analogue before rituximab therapy. Patients received a median of 4.0 (1-11.3) infusions of rituximab (375 mg/m2). Three patients received steroids with their infusions for prophylaxis of rituximab-related infusion syndrome. Overall, treatment was well tolerated. Median immunoglobulin M (IgM) levels for all patients declined from 2,403 mg/dL (range 720-7639 mg/dL) to 1,525 mg/dL (range 177-5,063 mg/dL) after rituximab therapy (p = 0.001), with 8 of 30 (27%) and 18 of 30 (60%) patients demonstrating >50% and >25% decline in IgM, respectively. Median bone marrow lymphoplasmacytic (BM LPC) cell involvement declined from 60% (range 5-90%) to 15% (range 0-80%) for 17 patients for whom pre-and post-BM biopsies were performed (p < 0.001). Moreover, 19 of 30 (63%) and 15 of 30 (50%) patients had an increase in their hematocrit (HCT) and platelet (PLT) counts, respectively. Before rituximab therapy, 7 of 30 (23.3%) patients were either transfusion or erythropoietin dependent, whereas only 1/30 (3.3%) patients required transfusions (no erythropoietin) after rituximab. Overall responses after treatment with rituximab were as follows: 8 (27%) and 10 (33%) of the patients achieved a partial (PR) and a minor (MR) response, respectively, and an additional 9 (30%) of patients demonstrated stable disease (SD). No patients attained a complete response. The median time to

  16. Antibody-based treatment of acute myeloid leukaemia.

    PubMed

    Mulford, Deborah A; Jurcic, Joseph G

    2004-01-01

    Monoclonal antibodies have become an important treatment modality in cancer therapy. Genetically engineered chimaeric and humanised antibodies have demonstrated activity against a variety of tumours. Whereas the humanised anti-CD33 monoclonal antibody HuM195 has only modest activity against overt acute myeloid leukaemia (AML), it can eliminate minimal residual disease detectable by reverse transcription-polymerase chain reaction in acute promyelocytic leukaemia. High-dose radioimmunotherapy with beta-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of antileukaemic therapy before bone marrow transplantation. Conversely, alpha-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumour cell kill while sparing surrounding normal cells. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy in the treatment of newly diagnosed AML. PMID:14680472

  17. Bispecific antibodies.

    PubMed

    Kontermann, Roland E; Brinkmann, Ulrich

    2015-07-01

    Bispecific antibodies (bsAbs) combine specificities of two antibodies and simultaneously address different antigens or epitopes. BsAbs with 'two-target' functionality can interfere with multiple surface receptors or ligands associated, for example with cancer, proliferation or inflammatory processes. BsAbs can also place targets into close proximity, either to support protein complex formation on one cell, or to trigger contacts between cells. Examples of 'forced-connection' functionalities are bsAbs that support protein complexation in the clotting cascade, or tumor-targeted immune cell recruiters and/or activators. Following years of research and development (R&D), the first bsAb was approved in 2009. Another bsAb entered the market in December 2014 and several more are in clinical trials. Here, we describe the potentials of bsAbs to become the next wave of antibody-based therapies, focusing on molecules in clinical development. PMID:25728220

  18. Brain Abscess following Rituximab Infusion in a Patient with Pemphigus Vulgaris

    PubMed Central

    Al-Harbi, Talal M.; Muammer, Shahad A.; Ellis, Ronald J.

    2015-01-01

    Patient: Female, 52 Final Diagnosis: Brain abscess Symptoms: Fever • headache • weakness, left sided Medication: Prednisolone • Azathioprine • Rituximab Clinical Procedure: Stereotactic brain biopsy and LP Specialty: Neurology Objective: Rare disease Background: Immunocompromised patients are at increased risk for developing meningitis or, rarely, brain abscess with opportunistic organisms like Listeria monocytogenes. Case Report: A 52 year-old Saudi Arabian woman who was diagnosed with pemphigus vulgaris and diabetes and had been on prednisolone and azathioprine for about 4 years. She presented with headache, low-grade fever, and left-sided weakness 2 weeks after receiving the second dose of rituximab infusion. Magnetic resonance imaging revealed an enhanced space-occupying lesion with multiple small cyst-like structures and vasogenic edema in the right temporoparietal area. Her blood culture was positive for Listeria monocytogenes, and a brain biopsy showed necrotic tissues with pus and inflammatory cells. She recovered after a 6-week course of antibiotics with ampicillin and gentamycin. Conclusions: Brain abscess due to Listeria monocytogenes is a risk that should be considered when adding rituximab to the regimen of a patient who is already Immunocompromised. PMID:25659437

  19. Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration

    PubMed Central

    Fathallah, Anas M.; Turner, Michael R.; Balu-Iyer, Sathy V.

    2015-01-01

    Subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after sc administration remains a major challenge. In this work we investigated the effects of excipient dependent hyper-osmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as our animal model, we compared the effects of NaCl, mannitol and, O-Phospho-L-Serine (OPLS) on plasma concentration of rituximab over 5 days after sc administration. We observed an increase in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, as compared to isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph node in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatic, as estimated by the model, increased from 0.05 % in isotonic buffer to 13% in hyper-tonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. Our data suggests that hypertonic solutions may be a viable option to improve sc bioavailability. PMID:25377184

  20. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia

    PubMed Central

    Branagan, Andrew R.; Ioakimidis, Leukothea; Soumerai, Jacob D.; Patterson, Christopher J.; Turnbull, Barry; Wasi, Parveen; Emmanouilides, Christos; Frankel, Stanley R.; Lister, Andrew; Morel, Pierre; Matous, Jeffrey; Gregory, Stephanie A.; Kimby, Eva

    2009-01-01

    We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m2 per day for 5 days) of fludarabine and 8 infusions (375 mg/m2 per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non–Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800. PMID:19015393

  1. Recurrence of light chain deposit disease after renal allograft transplantation: potential role of rituximab?

    PubMed

    Kuypers, Dirk R J; Lerut, Evelyne; Claes, Kathleen; Evenepoel, Pieter; Vanrenterghem, Yves

    2007-04-01

    Light chain deposit disease (LCDD) is a monoclonal plasma cell disorder characterized by tissue deposition of nonamyloid immunoglobulin light chains, predominantly kappa chains, causing renal insufficiency. LCDD reoccurs almost invariably after renal grafting, leading to early graft loss, usually within a time span of months to years. We describe a female patient with LCDD who lost her first living donor graft after 1 year due to extensive recurrence of kappa chain deposition. Rituximab was administered on the seventh day after her second transplantation with a graft from a deceased donor, in order to prevent early recurrence of LCDD. The 2-year protocol biopsy - similarly to the completely normal 1-year protocol biopsy - revealed persistent absence of light chain deposition on light microscopy but immunohistochemical staining and electron microscopy showed very mild recurrence of light chain deposits. A second 4-week course of rituximab was repeated because of these electron microscopic findings. Subsequently, free kappa light chain concentration decreased from 693 to 74 mg/l and remained low 4 months after completion of therapy. Rituximab could be considered for delaying early LCDD recurrence in patients in whom treatment of the underlying bone marrow disorder failed or is contraindicated, but maintenance therapy is apparently necessary to consolidate this response. PMID:17326779

  2. Prognostic model for mantle cell lymphoma in the rituximab era: a nationwide study in Japan.

    PubMed

    Chihara, Dai; Asano, Naoko; Ohmachi, Ken; Kinoshita, Tomohiro; Okamoto, Masataka; Maeda, Yoshinobu; Mizuno, Ishikazu; Matsue, Kosei; Uchida, Toshiki; Nagai, Hirokazu; Nishikori, Momoko; Nakamura, Shigeo; Ogura, Michinori; Suzuki, Ritsuro

    2015-09-01

    Mantle cell lymphoma (MCL) is essentially incurable with conventional chemotherapy. The MCL International Prognostic Index (MIPI) is a validated specific prognostic index, but was derived from patients with advanced-stage disease primarily in the pre-rituximab era. We analysed 501 MCL patients (median age, 67 years; range 22-90) treated with rituximab-containing chemotherapy, and evaluated the prognostic factors adjusted by the treatment. Five-year overall survival (OS) in the low, intermediate and high MIPI groups was 74%, 70% and 35%, respectively. Additional to MIPI risk factors, multivariate analysis revealed that low serum albumin and bone-marrow involvement were also significantly associated with a poor outcome. The revised-MIPI (R-MIPI) was constructed using six factors, namely age, performance status, white blood cell count, serum lactate dehydrogenase, bone-marrow involvement and serum albumin, which is divided into four prognostic groups. Five-year OS in low, low-intermediate (L-I), high-intermediate (H-I) and high R-MIPI groups was 92%, 75%, 61% and 19%, respectively. Hazard ratio for OS of L-I, H-I and high risk to low risk patients were 5·4, 8·3 and 33·0, respectively. R-MIPI, a new prognostic index with easy application to the general patient population, shows promise for identifying low- and high-risk MCL patients in the rituximab era. PMID:25953436

  3. Beneficial Effect of Rituximab in the Treatment of Recurrent Idiopathic Membranous Nephropathy after Kidney Transplantation

    PubMed Central

    Sprangers, Ben; Lefkowitz, George Ian; Cohen, Scott D.; Stokes, Michael Barry; Valeri, Antony; Appel, Gerald B.

    2010-01-01

    Background and objectives: Recurrence of the original kidney disease after renal transplantation is an increasingly recognized cause of allograft loss. Idiopathic membranous nephropathy (iMN) is a common cause of proteinuria that may progress to ESRD. It is known that iMN may recur after kidney transplantation, causing proteinuria, allograft dysfunction, and allograft loss. Limited data regarding the frequency and treatment of recurrent iMN are available. Design, setting, participants, & measurements: In this single-center study, all patients who had iMN and were receiving a first kidney transplant were included. We retrospectively assessed the incidence of biopsy-confirmed recurrent iMN and compared clinical characteristics of patients with and without recurrence. In addition, the effect of treatment with rituximab on proteinuria and renal allograft function in patients with recurrent iMN was examined Results: The incidence of recurrent iMN was 44%, and recurrences occurred at a median time of 13.6 months after transplantation. Two patterns of recurrence were identified: Early and late. No predictors of recurrence or disease progression could be identified. Treatment with rituximab was effective in four of four patients in stabilizing or reducing proteinuria and stabilizing renal function. Conclusions: Recurrence of iMN is common even in the era of modern immunosuppression. Rituximab seems to be a valuable treatment option for these patients, although lager studies are needed to confirm our data. PMID:20185599

  4. Anti-Apoptotic Effects of Lentiviral Vector Transduction Promote Increased Rituximab Tolerance in Cancerous B-Cells

    PubMed Central

    Ranjbar, Benyamin; Krogh, Louise Bechmann; Laursen, Maria Bach; Primo, Maria Nascimento; Marques, Sara Correia; Dybkær, Karen; Mikkelsen, Jacob Giehm

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is characterized by great genetic and clinical heterogeneity which complicates prognostic prediction and influences treatment efficacy. The most common regimen, R-CHOP, consists of a combination of anthracycline- and immuno-based drugs including Rituximab. It remains elusive how and to which extent genetic variability impacts the response and potential tolerance to R-CHOP. Hence, an improved understanding of mechanisms leading to drug tolerance in B-cells is crucial, and modelling by genetic intervention directly in B-cells is fundamental in such investigations. Lentivirus-based gene vectors are widely used gene vehicles, which in B-cells are an attractive alternative to potentially toxic transfection-based methodologies. Here, we investigate the use of VSV-G-pseudotyped lentiviral vectors in B-cells for exploring the impact of microRNAs on tolerance to Rituximab. Notably, we find that robust lentiviral transduction of cancerous B-cell lines markedly and specifically enhances the resistance of transduced germinal center B-cells (GCBs) to Rituximab. Although Rituximab works partially through complement-mediated cell lysis, increased tolerance is not achieved through effects of lentiviral transduction on cell death mediated by complement. Rather, reduced levels of PARP1 and persistent high levels of CD43 in Rituximab-treated GCBs demonstrate anti-apoptotic effects of lentiviral transduction that may interfere with the outcome and interpretation of Rituximab tolerance studies. Our findings stress that caution should be exercised exploiting lentiviral vectors in studies of tolerance to therapeutics in DLBCL. Importantly, however, we demonstrate the feasibility of using the lentiviral gene delivery platform in studies addressing the impact of specific microRNAs on Rituximab responsiveness. PMID:27045839

  5. Advances in Immuno–Positron Emission Tomography: Antibodies for Molecular Imaging in Oncology

    PubMed Central

    Knowles, Scott M.; Wu, Anna M.

    2012-01-01

    Identification of cancer cell–surface biomarkers and advances in antibody engineering have led to a sharp increase in the development of therapeutic antibodies. These same advances have led to a new generation of radiolabeled antibodies and antibody fragments that can be used as cancer-specific imaging agents, allowing quantitative imaging of cell-surface protein expression in vivo. Immuno–positron emission tomography (immunoPET) imaging with intact antibodies has shown success clinically in diagnosing and staging cancer. Engineered antibody fragments, such as diabodies, minibodies, and single-chain Fv (scFv) –Fc, have been successfully employed for immunoPET imaging of cancer cell–surface biomarkers in preclinical models and are poised to bring same-day imaging into clinical development. ImmunoPET can potentially provide a noninvasive approach for obtaining target-specific information useful for titrating doses for radioimmunotherapy, for patient risk stratification and selection of targeted therapies, for evaluating response to therapy, and for predicting adverse effects, thus contributing to the ongoing development of personalized cancer treatment. PMID:22987087

  6. Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome.

    PubMed

    Ruggenenti, Piero; Ruggiero, Barbara; Cravedi, Paolo; Vivarelli, Marina; Massella, Laura; Marasà, Maddalena; Chianca, Antonietta; Rubis, Nadia; Ene-Iordache, Bogdan; Rudnicki, Michael; Pollastro, Rosa Maria; Capasso, Giovambattista; Pisani, Antonio; Pennesi, Marco; Emma, Francesco; Remuzzi, Giuseppe

    2014-04-01

    The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children. PMID:24480824

  7. MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models.

    PubMed

    Gu, Juan J; Hernandez-Ilizaliturri, Francisco J; Mavis, Cory; Czuczman, Natalie M; Deeb, George; Gibbs, John; Skitzki, Joseph J; Patil, Ritesh; Czuczman, Myron S

    2013-11-01

    To further develop therapeutic strategies targeting the proteasome system, we studied the antitumor activity and mechanisms of action of MLN2238, a reversible proteasome inhibitor, in preclinical lymphoma models. Experiments were conducted in rituximab-chemotherapy-sensitive cell lines, rituximab-chemotherapy-resistant cell lines (RRCL), and primary B-cell lymphoma cells. Cells were exposed to MLN2238 or caspase-dependent inhibitors, and differences in cell viability, alterations in apoptotic protein levels, effects on cell cycle, and the possibility of synergy when combined with chemotherapeutic agents were evaluated. MLN2238 showed more potent dose-dependent and time-dependent cytotoxicity and inhibition of cell proliferation in lymphoma cells than bortezomib. Our data suggest that MLN2238 can induce caspase-independent cell death in RRCL. MLN2238 (and to a much lesser degree bortezomib) reduced RRCL S phase and induced cell cycle arrest in the G2/M phase. Exposure of rituximab-chemotherapy-sensitive cell lines and RRCL to MLN2238 potentiated the cytotoxic effects of gemcitabine, doxorubicin, and paclitaxel and overcame resistance to chemotherapy in RRCL. MLN2238 is a potent proteasome inhibitor active in rituximab-chemotherapy-sensitive and rituximab-chemotherapy-resistant cell models and potentiates the antitumor activity of chemotherapy agents and has the potential of becoming an effective therapeutic agent in the treatment of therapy-resistant B-cell lymphoma. PMID:23995855

  8. Low Incidence of Radionecrosis in Children Treated with Conventional Radiation Therapy and Intrathecal Radioimmunotherapy

    PubMed Central

    Kramer, Kim; Pandit-Taskar, Neeta; Zanzonico, Pat; Wolden, Suzanne L.; Humm, John L.; DeSelm, Carl; Souweidane, Mark M.; Lewis, Jason S.; Cheung, Nai-Kong. V.

    2015-01-01

    Radionecrosis is a potentially devastating complication of external beam radiotherapy (XRT). Intraventricular compartmental radioimmunotherapy (cRIT) using 131I-3F8 or 131I-8H9 can eradicate malignant cells in the CSF. The incidence of radionecrosis using cRIT 131I based intraventricular radioiimunotherapy, when used alone or in combination with conventional craniospinal CSI-XRT is unknown. We retrospectively analyzed the incidence of radionecrosis in 2 cohorts of pediatric patients treated with both CSI-XRT and cRIT at MSKCC since 2003: patients with metastatic CNS neuroblastoma (NB) and medulloblastoma (MB). 94 patients received both CSI-XRT and cRIT, 2 received cRIT alone, median follow up 41.5 months (6.5–124.8 months). Mean CSI-XRT dose was 28 Gy (boost to the primary tumor site up to 54 Gy) in the MB cohort, and CSI XRT dose 18–21 Gy (boost to 30 Gy for focal parenchymal mass) in the NB cohort. For MB patients, 20% had focal re-irradiation for a second or more subsequent relapse, mean repeat-XRT dose was 27.5 Gy; 7 patients with NB had additional focal XRT. Median CSF cRIT dose was 18.6 Gy in the MB cohort and 32.1 in the NB cohort. One asymptomatic patient underwent resection of 0.6-cm hemorrhagic periventricular white-matter lesion confirmed to be necrosis and granulation tissue, 2.5 years after XRT. The risk of radionecrosis in children treated with XRT and cRIT appears minimal (~1%). No neurologic deficits secondary to radionecrosis have been observed in long-term survivors treated with both modalities, including patients who underwent re-XRT. Administration of cRIT may safely proceed in patients treated with conventional radiotherapy without appearing to increase the risk of radionecrosis. PMID:25944385

  9. SU-E-J-03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

    SciTech Connect

    Huang, C.Y.; Guatelli, S; Oborn, B; Allen, B

    2014-06-01

    Purpose: The purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors. Methods: Because of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 based microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes ({sup 211}At, {sup 213}Bi, {sup 223}Ra and {sup 225}Ac) and 6 beta emitters ({sup 32}P, {sup 33}P, {sup 67}Cu, {sup 90}Y, {sup 131}I and {sup 177}Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters. Results: We show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors. Conclusion: The results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development.

  10. Dosimetric model for intraperitoneal targeted liposomal radioimmunotherapy of ovarian cancer micrometastases.

    PubMed

    Syme, A M; McQuarrie, S A; Middleton, J W; Fallone, B G

    2003-05-21

    A simple model has been developed to investigate the dosimetry of micrometastases in the peritoneal cavity during intraperitoneal targeted liposomal radioimmunotherapy. The model is applied to free-floating tumours with radii between 0.005 cm and 0.1 cm. Tumour dose is assumed to come from two sources: free liposomes in solution in the peritoneal cavity and liposomes bound to the surface of the micrometastases. It is assumed that liposomes do not penetrate beyond the surface of the tumours and that the total amount of surface antigen does not change over the course of treatment. Integrated tumour doses are expressed as a function of biological parameters that describe the rates at which liposomes bind to and unbind from the tumour surface, the rate at which liposomes escape from the peritoneal cavity and the tumour surface antigen density. Integrated doses are translated into time-dependent tumour control probabilities (TCPs). The results of the work are illustrated in the context of a therapy in which liposomes labelled with Re-188 are targeted at ovarian cancer cells that express the surface antigen CA-125. The time required to produce a TCP of 95% is used to investigate the importance of the various parameters. The relative contributions of surface-bound radioactivity and unbound radioactivity are used to assess the conditions required for a targeted approach to provide an improvement over a non-targeted approach during intraperitoneal radiation therapy. Using Re-188 as the radionuclide, the model suggests that, for microscopic tumours, the relative importance of the surface-bound radioactivity increases with tumour size. This is evidenced by the requirement for larger antigen densities on smaller tumours to affect an improvement in the time required to produce a TCP of 95%. This is because for the smallest tumours considered, the unbound radioactivity is often capable of exerting a tumouricidal effect before the targeting agent has time to accumulate

  11. Successful radioimmunotherapy for micro and occult metastases in a SCID mouse model

    SciTech Connect

    Yokoyama, K.; Koshida, K.; Kinuya, S. |

    1996-05-01

    It is often addressed that the most appropriate candidate, theoretically, for radioimmunotherapy (RIT) is not bulky tumor burden but for micro or occult metastatic foci, The major obstacles in the verification for veracious efficacy of RIT had been clinically and preclinically the difficulty in obtaining such a model. We have developed the model of testicular tumor (primary site) with visible small metastases to the lymph nodes (LNs) and non-visible (occult) lesions to distant organs in severe combined immunodeficient (SCID) mice. And thus, the suppression of minute tumor depositions after RIT was evaluated. One week after hemilateral intratesticular injection of 2 million of HELA Hep 2 cells that expressed placental alkaline phosphatase (PLAP), the group of the mice were treated with a single dose of I-131 labeled HPMS-1, anti-PLAP MoAb or with saline control. The I-131 labeled HPMS-1 (5.6 MBq / 150 {mu}g) was intravenously administered and at 2 weeks after, the testis, retroperitoneal and intraperitoneal LNs and other gans were removed. For the control group, the testicular tumor and LNs metastases were found in 100% and 86% of the mice. The metastases in the liver and lung were not observed by histological examination but in all mouse samples, the PCR (polymerase chain reaction) assay could identify the human {beta}-globin gene derived from HeLa cells, indicating the presence of definitive metastases. For the treated group, the average testicular tumor weight was significantly reduced by the factor of 2.4 (132 mg vs 311 mg, p<0.01). The LNs metastases were even more distinctively suppressed by the factor of 45.7 (13 mg vs 599 mg, p,0.05). Remarkably, the PCR products from the occult metastases were almost completely controlled; 97% suppression found for the liver and 81% for the lung. Thus, we conclude that using I-131 as a label, RIT is justified to used for targeting and killing minute tumor foci.

  12. Antibody-Mediated Autoimmune Encephalopathies and Immunotherapies.

    PubMed

    Gastaldi, Matteo; Thouin, Anaïs; Vincent, Angela

    2016-01-01

    Over the last 15 years it has become clear that rare but highly recognizable diseases of the central nervous system (CNS), including newly identified forms of limbic encephalitis and other encephalopathies, are likely to be mediated by antibodies (Abs) to CNS proteins. The Abs are directed against membrane receptors and ion channel-associated proteins that are expressed on the surface of neurons in the CNS, such as N-methyl D-aspartate receptors and leucine-rich, glioma inactivated 1 protein and contactin-associated protein like 2, that are associated with voltage-gated potassium channels. The diseases are not invariably cancer-related and are therefore different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, Abs to intracellular proteins. Most importantly, the new antibody-associated diseases almost invariably respond to immunotherapies with considerable and sometimes complete recovery, and there is convincing evidence of their pathogenicity in the relatively limited studies performed so far. Treatments include first-line steroids, intravenous immunoglobulins, and plasma exchange, and second-line rituximab and cyclophosphamide, followed in many cases by steroid-sparing agents in the long-term. This review focuses mainly on N-methyl D-aspartate receptor- and voltage-gated potassium channel complex-related Abs in adults, the clinical phenotypes, and treatment responses. Pediatric cases are referred to but not reviewed in detail. As there have been very few prospective studies, the conclusions regarding immunotherapies are based on retrospective studies. PMID:26692392

  13. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma.

    PubMed

    Boland, A; Bagust, A; Hockenhull, J; Davis, H; Chu, P; Dickson, R

    2009-09-01

    This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (NHL), in accordance with the licensed indication, based upon the evidence submission from Roche Products Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence included two randomised controlled trials [European Organisation for Research and Treatment of Cancer (EORTC) and German Low Grade Lymphoma Study Group - Fludarabine, Cyclophosphamide and Mitoxantrone and (GLSG-FCM)] comparing the clinical effects of chemotherapy with or without rituximab in the induction of remission at first or second relapse and the clinical benefits of rituximab maintenance therapy versus the NHS's current clinical practice of observation for follicular lymphoma (FL) patients. Both trials showed that in patients with relapsed FL the addition of rituximab to chemotherapy induction treatment increased overall response rates. Furthermore, rituximab maintenance therapy increased the median length of remission when compared with observation only. Safety data from the two trials showed that while the majority of patients reported some adverse events, the number of patients withdrawing from treatment in the EORTC trial was low, with rates not being reported for the GLSG-FCM trial. The most commonly reported adverse events were blood/bone marrow toxicity, skin rashes and allergies. The ERG reran the manufacturer's economic model after altering several of the assumptions and parameter values in order to recalculate the cost-utility ratios, quality-adjusted life-years (QALYs) and estimates of benefits. The manufacturer reported that maintenance therapy with rituximab was cost-effective compared with observation against commonly applied thresholds, with an incremental

  14. In vitro characterization of 211 At-labeled antibody A33--a potential therapeutic agent against metastatic colorectal carcinoma.

    PubMed

    Almqvist, Ylva; Orlova, Anna; Sjöström, Anna; Jensen, Holger J; Lundqvist, Hans; Sundin, Anders; Tolmachev, Vladimir

    2005-10-01

    The humanized antibody A33 binds to the A33 antigen, expressed in 95% of primary and metastatic colorectal carcinomas. The restricted pattern of expression in normal tissue makes this antigen a possible target for radioimmunotherapy of colorectal micrometastases. In this study, the A33 antibody was labeled with the therapeutic nuclide (211)At using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB). The in vitro characteristics of the (211)At-benzoate-A33 conjugate ((211)At-A33) were investigated and found to be similar to those of (125)I-benzoate-A33 ((125)I-A33) in different assays. Both conjugates bound with high affinity to SW1222 cells (K(d) = 1.7 +/- 0.2 nM, and 1.8 +/- 0.1 nM for (211)At-A33 and (125)I-A33, respectively), and both showed good intracellular retention (70% of the radioactivity was still cell associated after 20 hours). The cytotoxic effect of (211)At-A33 was also confirmed. After incubation with (211)At-A33, SW1222 cells had a survival of approximately 0.3% when exposed to some 150 decays per cell (DPC). The cytotoxic effect was found to be dose-dependent, as cells exposed to only 56 DPC had a survival of approximately 5%. The (211)At-A33 conjugate shows promise as a potential radioimmunotherapy agent for treatment of micrometastases originating from colorectal carcinoma. PMID:16248767

  15. Antithyroid microsomal antibody

    MedlinePlus

    ... Thyroid antimicrosomal antibody; Antimicrosomal antibody; Microsomal antibody; Thyroid peroxidase antibody; TPOAb Images Blood test References Guber HA, Faraq AF. Evaluation of endocrine function. In: McPherson RA, Pincus MR, eds. Henry's Clinical ...

  16. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wen, Sijin; Wierda, William G.; O'Brien, Susan M.; Faderl, Stefan; Sargent, Rachel; Burger, Jan A.; Ferrajoli, Alessandra

    2013-01-01

    Purpose Lenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL. Patients and Methods Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m2 intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically. Results The overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study. Conclusion The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation. PMID:23270003

  17. Safety and efficacy of intrathecal rituximab in children with B cell lymphoid CD20+ malignancies: An international retrospective study.

    PubMed

    Ceppi, Francesco; Weitzman, Sheila; Woessmann, Wilhelm; Davies, Kimberly; Lassaletta, Alvaro; Reismüller, Bettina; Mellgren, Karin; Uyttebroeck, Anne; Maia, Iris; Abdullah, Shaker; Miakova, Natasha; Glaser, Darryl; Cohn, Richard; Abla, Oussama; Attarbaschi, Andishe; Alexander, Sarah

    2016-05-01

    Central nervous system (CNS) involvement in patients with mature B non-Hodgkin lymphoma, post-transplantation proliferative disorder and acute lymphoblastic leukemia confers a significantly inferior prognosis as compared to patients without CNS disease. Intrathecal (IT) or intraventricular administration of rituximab is an option for this group of patients. We report 25 children with CNS involvement of CD20+ B lymphoid malignancies who received in total 163 IT/intraventricular rituximab doses. The median number of doses received by each patient was 6, with a median dose of 25 mg. The most common adverse events were Grades 1 and 2 peripheral neuropathies in five patients (20%), allergy in two patients, and headache in two patients. These events were self-limited, occurring in the 48 hours after treatment and resolving within 24 hr. Three patients presented with more severe though transient side effects, one with a Grade III neuropathy and two with seizure. Eighteen patients (72%) of those treated with IT/intraventricular rituximab, with or without other CNS directed treatment, achieved a CNS remission. This case series suggests that IT/intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Prospective trials of IT/intraventricular rituximab for patients with CNS involvement of CD20 + B lymphoid malignancies are warranted. Am. J. Hematol. 91:486-491, 2016. © 2016 Wiley Periodicals, Inc. PMID:26872652

  18. Efficacy and safety of rituximab therapy for systemic lupus erythematosus: a systematic review and meta-analysis

    PubMed Central

    Lan, Lan; Han, Fei; Chen, Jiang-hua

    2012-01-01

    Objective: To review the efficacy and safety of rituximab therapy for systemic lupus erythematosus (SLE).Methods: We searched for randomized controlled trails and observational studies that evaluated the effect of rituximab based on the systemic lupus erythematosus disease activity index (SLEDAI), British Isles lupus assessment group index (BILAG), urine protein levels, and the prednisolone dose, and had adequate data to calculate the mean, standard deviation (SD), and 95% confidence intervals, and to systematically review and meta-analyze observational studies with fixed effects model or random effects model. Results: We included 2 randomized controlled studies and 19 observational clinical studies. We summarized the data from the 19 observational studies, analyzed the heterogeneity of the literature, and then used fixed effect model or random effect model for statistical analysis. The SLEDAI, BILAG, and urine protein levels and the prednisolone dosage were decreased after rituximab treatment, and the decreases in the BILAG, urine protein levels, and the prednisolone dose were found to be significant (P<0.05), when compared with baseline level. Rituximab’s adverse effects generally could be controlled with an effective dosing regimen. Conclusions: Although there are still controversies about rituximab’s treatment on SLE, but our study had showed that rituximab had favorable effects on refractory lupus. The long-term efficacy and safety of rituximab require further study. PMID:22949364

  19. Different sensitivity of rituximab-treatment to B-cells between ABO-incompatible kidney and liver transplantation.

    PubMed

    Morimoto, Hiroshi; Ide, Kentaro; Tanaka, Yuka; Ishiyama, Kohei; Ohira, Masahiro; Tahara, Hiroyuki; Akita, Tomonori; Tanaka, Junko; Ohdan, Hideki

    2016-06-01

    A desensitization protocol with rituximab is currently widely used for kidney transplantation (KT) and liver transplantation (LT) across the ABO blood group-incompatible (ABO-I) barrier. However, it remains to be elucidated whether rituximab is equally effective for B-cell and T-cell immune responses in both KT and LT recipients. To clarify these effects of rituximab, we enrolled 46 KT and 77 LT recipients in this study. The proportion of peripheral blood B-cells was determined at the perioperative period. T-cell responses to allostimulation were evaluated by a mixed lymphocyte reaction (MLR) assay. One week after rituximab administration, peripheral B-cells became undetectable in ABO-I KT recipients but remained detectable in some of the ABO-I LT recipients; B-cells were undetectable in both groups by week 2. B-cells remained below the detection limit throughout the first year in the ABO-I KT recipients, whereas they reappeared in the periphery after 6months in the ABO-I LT recipients. There were no significant differences in alloreactive T-cell responses based on MLR analyses between ABO-I and ABO-compatible groups. This study indicates that rituximab has differing B-cell sensitivity between KT and LT recipients and a minimal effect on the alloreactive T-cell responses in KT and LT recipients. PMID:27085793

  20. A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys

    PubMed Central

    Smith, Eric J.; Olson, Kara; Haber, Lauric J.; Varghese, Bindu; Duramad, Paurene; Tustian, Andrew D.; Oyejide, Adelekan; Kirshner, Jessica R.; Canova, Lauren; Menon, Jayanthi; Principio, Jennifer; MacDonald, Douglas; Kantrowitz, Joel; Papadopoulos, Nicholas; Stahl, Neil; Yancopoulos, George D.; Thurston, Gavin; Davis, Samuel

    2015-01-01

    Bispecific antibodies, while showing great therapeutic potential, pose formidable challenges with respect to their assembly, stability, immunogenicity, and pharmacodynamics. Here we describe a novel class of bispecific antibodies with native human immunoglobulin format. The design exploits differences in the affinities of the immunoglobulin isotypes for Protein A, allowing efficient large-scale purification. Using this format, we generated a bispecific antibody, REGN1979, targeting the B cell marker, CD20, and the CD3 component of the T cell receptor, which triggers redirected killing of B cells. In mice, this antibody prevented growth of B cell tumors and also caused regression of large established tumors. In cynomolgus monkeys, low doses of REGN1979 caused prolonged depletion of B cells in peripheral blood with a serum half-life of approximately 14 days. Further, the antibody induced a deeper depletion of B cells in lymphoid organs than rituximab. This format has broad applicability for development of clinical bispecific antibodies. PMID:26659273

  1. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project

    PubMed Central

    Carson, Kenneth R.; Evens, Andrew M.; Richey, Elizabeth A.; Habermann, Thomas M.; Focosi, Daniele; Seymour, John F.; Laubach, Jacob; Bawn, Susie D.; Gordon, Leo I.; Winter, Jane N.; Furman, Richard R.; Vose, Julie M.; Zelenetz, Andrew D.; Mamtani, Ronac; Raisch, Dennis W.; Dorshimer, Gary W.; Rosen, Steven T.; Muro, Kenji; Gottardi-Littell, Numa R.; Talley, Robert L.; Sartor, Oliver; Green, David; Major, Eugene O.

    2009-01-01

    Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons. PMID:19264918

  2. α-Imaging Confirmed Efficient Targeting of CD₄₅-Positive Cells After ²¹¹At-Radioimmunotherapy for Hematopoietic Cell Transplantation

    SciTech Connect

    Frost, Sophia; Miller, Brian W.; Back, Tom; Santos, E. B.; Hamlin, Donald K.; Knoblaugh, E.; Frayo, Shani; Kenoyer, Aimee L.; Storb, Rainer; Press, O. W.; Wilbur, D. Scott; Pagel, John M.; Sandmaier, B. M.

    2015-09-03

    Alpha-radioimmunotherapy (α-RIT) targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-²¹¹(²¹¹At)-RIT, extending the analysis to include intra-organ ²¹¹At activity distribution and α-imaging-based small-scale dosimetry, along with imunohistochemical staining. Methods: Eight normal dogs were injected with either 0.75 (n=5) or 1.00 mg/kg (n=3) of ²¹¹At-B10-CA12.10C12 (11.5–27.6 MBq/kg). Two were euthanized and necropsied 19–22 hours postinjection (p.i.), and six received autologous HCT three days after ²¹¹At-RIT, following lymph node and bone marrow biopsies at 2–4 and/or 19 hours p.i. Blood was sampled to study toxicity and clearance; CD45 targeting was evaluated by flow cytometry. ²¹¹At localization and small scale dosimetry were assessed using two α-imaging : α-camera and iQID. Results: Uptake of ²¹¹At was highest in spleen (0.31–0.61 %IA/g), lymph nodes (0.02–0.16 %IA/g), liver (0.11–0.12 %IA/g), and marrow (0.06–0.08 %IA/g). Lymphocytes in blood and marrow were efficiently targeted using either MAb dose. Lymph nodes remained unsaturated, but displayed targeted ²¹¹At localization in T lymphocyte-rich areas. Absorbed doses to blood, marrow, and lymph nodes were estimated at 3.9, 3.0, and 4.2 Gy/210 MBq, respectively. All transplanted dogs experienced transient hepatic toxicity. Liver enzyme levels were temporarily elevated in 5 of 6 dogs; 1 treated with 1.00 mg MAb/kg developed ascites and was euthanized 136 days after HCT. Conclusion: ²¹¹At-anti-CD45 RIT with 0.75 mg MAb/kg efficiently targeted blood and marrow without severe toxicity. Dosimetry calculations and observed radiation-induced effects indicated that sufficient ²¹¹At-B10-CA12.10C12 localization was achieved for efficient conditioning for HCT.

  3. Glomerular filtration rate after alpha-radioimmunotherapy with 211At-MX35-F(ab')2: a long-term study of renal function in nude mice.

    PubMed

    Bäck, Tom; Haraldsson, Börje; Hultborn, Ragnar; Jensen, Holger; Johansson, Martin E; Lindegren, Sture; Jacobsson, Lars

    2009-12-01

    Besides bone marrow, the kidneys are often dose-limiting organs in internal radiotherapy. The effects of high-linear energy transfer (LET) radiation on the kidneys after alpha-radioimmunotherapy (alpha-RIT) with the alpha-particle emitter, (211)At, were studied in nude mice by serial measurements of the glomerular filtration rate (GFR). The renal toxicity was evaluated at levels close to the dose limit for the bone marrow and well within the range for therapeutic efficacy on tumors. Astatinated MX35-F(ab')(2) monoclonal antibodies were administered intravenously to nude mice. Both non-tumor-bearing animals and animals bearing subcutaneous xenografts of the human ovarian cancer cell line, OVCAR-3, were used. The animals received approximately 0.4, 0.8, or 1.2 MBq in one, two, or three fractions. The mean absorbed doses to the kidneys ranged from 1.5 to 15 Gy. The renal function was studied by serial GFR measurements, using plasma clearance of (51)Cr-EDTA, up to 67 weeks after the first astatine injection. A dose-dependent effect on GFR was found and at the time interval 8-30 weeks after the first administration of astatine, the absorbed doses causing a 50% decrease in GFR were 16.4 +/- 3.3 and 14.0 +/- 4.1 Gy (mean +/- SEM), tumor- and non-tumor-bearing animals, respectively. The reduction in GFR progressed with time, and at the later time interval, (31-67 weeks) the corresponding absorbed doses were 7.5 +/- 2.4 and 11.3 +/- 2.3 Gy, respectively, suggesting that the effects of radiation on the kidneys were manifested late. Examination of the kidney sections showed histologic changes that were overall subdued. Following alpha-RIT with (211)At-MX35-F(ab')(2) at levels close to the dose limit of severe myelotoxicity, the effects found on renal function were relatively small, with only minor to moderate reductions in GFR. These results suggest that a mean absorbed dose to the kidneys of approximately 10 Gy is acceptable, and that the kidneys would not be the primary

  4. High-Dose 131I-Tositumomab (Anti-CD20) Radioimmunotherapy for Non-Hodgkin's Lymphoma: Adjusting Radiation Absorbed Dose to Actual Organ Volumes

    SciTech Connect

    Rajendran, Joseph G.; Fisher, Darrell R.; Gopal, A K.; Durack, L. D.; Press, O. W.; Eary, Janet F.

    2004-06-01

    Radioimmunotherapy (RIT) using 131I-tositumomab has been used successfully to treat relapsed or refractory B-cell non-Hodgin's lymphoma (NHL). Our approach to treatment planning has been to determine limits on radiation absorbed close to critical nonhematopoietic organs. This study demonstrates the feasibility of using CT to adjust for actual organ volumes in calculating organ-specific absorbed dose estimates. Methods: Records of 84 patients who underwent biodistribution studies after a trace-labeled infusion of 131I-tositumomab for RIT (January 1990 and April 2003) were reviewed. Serial planar -camera images and whole-body Nal probe counts were obtained to estimate 131I-antibody source-organ residence times as recommended by the MIRD Committee. The source-organ residence times for standard man or woman were adjusted by the ratio of the MIRD phantom organ mass to the CT-derived organ mass. Results: The mean radiation absorbed doses (in mGy/MBq) for our data using the MIRD model were lungs= 1.67; liver= 1.03; kidneys= 1.08; spleen= 2.67; and whole body= 0.3; and for CT volume-adjusted organ volumes (in mGy/MBq) were lungs= 1.30; liver= 0.92; kidneys= 0.76; spleen= 1.40; and whole body= 0.22. We determined the following correlation coefficients between the 2 methods for the various organs; lungs, 0.49; (P= 0.0001); liver, 0.64 (P= 0.004); kidneys, 0.45 (P= 0.0001), for the residence times. For therapy, patients received mean 131I administered activities of 19.2 GBq (520 mCi) after adjustment for CT-derived organ mass compared with 16.0 GBq (433 mCi) that would otherwise have been given had therapy been based only using standard MIRD organ volumes--a statistically significant difference (P= 0.0001). Conclusion: We observed large variations in organ masses among our patients. Our treatments were planned to deliver the maximally tolerated radiation dose to the dose-limiting normal organ. This work provides a simplified method for calculating patient-specific radiation

  5. Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting.

    PubMed

    Sehn, Laurie H; Donaldson, Jane; Filewich, Allison; Fitzgerald, Catherine; Gill, Karamjit K; Runzer, Nancy; Searle, Barb; Souliere, Sheila; Spinelli, John J; Sutherland, Judy; Connors, Joseph M

    2007-05-15

    The increasing usage of rituximab in the management of non-Hodgkin lymphoma (NHL) has created huge logistical challenges with respect to the delivery of this time- and labor-intensive drug. To address these challenges, we developed and tested the feasibility of a 90-minute infusion schedule for rituximab (20% of the dose administered in the first 30 minutes, remaining 80% administered over 60 minutes). A safety analysis performed in 150 patients receiving rituximab with corticosteroid-containing chemotherapy and 56 patients receiving rituximab as maintenance therapy demonstrated that this schedule was well tolerated, with no grade 3 or 4 infusion reactions observed. In addition, no increase in minor reactions was noted. More than 1200 patients have been treated with this rapid rituximab infusion schedule in the province of British Columbia (BC), demonstrating its safety in the community setting. The adoption of this 90-minute schedule as standard practice has had a positive impact on resource utilization. PMID:17244675

  6. [Successful treatment with rituximab in two cases of IgM-monoclonal gammopathy of undetermined significance (MGUS) neuropathy].

    PubMed

    Koike, Michiaki; Sugimoto, Keiji; Tusui, Miyuki; Yahata, Yuriko

    2012-04-01

    A 66-year-old male was hospitalized with muscle weakness and gait disturbance. Examination revealed IgM 3,407 mg/dl (IgM, κ-type M protein) and he was diagnosed as having IgM-MGUS neuropathy. He suffered from paralysis of respiratory muscles and required a respirator support. Plasmapheresis and intravenous immunoglobulin were performed and he was weaned from the respirator. Rituximab given as 8 weekly infusions improved gait disturbance. A 71-year-old male was hospitalized with lumbago, numbness of lower extremities and gait disturbance. Examination revealed IgM 1,553 mg/dl (IgM, λ-type M protein) and he was diagnosed with IgM-MGUS neuropathy. Rituximab given as 8 weekly infusions improved gait disturbance. It was concluded that rituximab is a well-tolerated treatment that may be effective in some patients with IgM-MGUS neuropathy. PMID:22687979

  7. Delayed-onset grade 4 neutropenia associated with rituximab therapy in a patient with lymphoma: case report and literature review.

    PubMed

    Motl, Susannah E; Baskin, Reed C

    2005-08-01

    A 53-year-old man developed delayed-onset neutropenia 6 weeks after completing first-line therapy with rituximab, cyclophosphamide, mitoxantrone, vincristine, and prednisone for high-grade B-cell lymphoma. Bone marrow biopsy demonstrated hypercellular marrow with normal maturation. He also developed interstitial pneumonitis, an adverse event associated with rituximab use. Infiltrates of T cells were found in the patient's lungs. For the next 6 months, the patient required subcutaneous granulocyte colony-stimulating factor 300 mug twice/week to maintain a granulocyte count above 1000 cells/mm3. He also received oral antibiotics for mouth sores and thrush. Based on the existing evidence, monitoring blood counts for as long as 8 weeks after rituximab therapy may be advisable, although the literature reports that neutropenia can develop up to 1 year after treatment. The development of a registry and uniform testing may help uncover the cause of this delayed-onset neutropenia. PMID:16207108

  8. Could we use a lower dose of rituximab to treat rheumatoid arthritis in clinical practice: pros and cons?

    PubMed

    Ferraccioli, Gianfranco; Tolusso, Barbara; Gremese, Elisa

    2016-01-01

    The CERERRA database provides evidence that low-dose rituximab performs as well as the conventional dose in the real world, thus highlighting the possible pharmacoeconomic impact. In clinical trials, it has been shown that rituximab 500 mg twice, performs as well as 1 g twice, 2 weeks apart, in terms of the American College of Rheumatology (ACR)20 and ACR50, but not the ACR70. The choice should always be made after considering that the IMAGE trial has demonstrated similar radiographic progression after the first 6 months, but with less control, with low-dose rituximab in the first 6 months. A possible alternative can be hypothesized. PMID:27255529

  9. Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells.

    PubMed

    Daneshmanesh, A H; Hojjat-Farsangi, M; Khan, A S; Jeddi-Tehrani, M; Akhondi, M M; Bayat, A A; Ghods, R; Mahmoudi, A-R; Hadavi, R; Österborg, A; Shokri, F; Rabbani, H; Mellstedt, H

    2012-06-01

    ROR1 is a receptor tyrosine kinase (RTK) recently identified to be overexpressed at the gene and protein levels in chronic lymphocytic leukemia (CLL). Monoclonal antibodies (MAbs) against RTKs have been successfully applied for therapy of solid tumors. We generated five MAbs against the Ig (n = 1), cysteine-rich (CRD) (n = 2) and kringle (KNG) (n = 2) domains, respectively, of the extracellular part of ROR1. All CLL patients (n = 20) expressed ROR1 on the surface of the leukemic cells. A significantly higher frequency of ROR1 expression was found in patients with progressive versus non-progressive disease, and in those with unmutated versus mutated IgVH genes. All five MAbs alone induced apoptosis in the absence of complement or added effector cells (Annexin-V and MTT, as well as cleavage of poly-(ADP ribose)-polymerase, caspase-8 and caspase-9) of CLL cells but not of normal B cells. Most effective were MAbs against CRD and KNG, significantly superior to rituximab (P < 0.005). Cross-linking of anti-ROR1 MAbs using the F(ab')(2) fragments of anti-Fc antibodies significantly augmented apoptosis. Two of the MAbs induced complement-dependent cytotoxicity (CDC) similar to that of rituximab and one anti-ROR1 MAb (KNG) (IgG1) showed killing activity by antibody-dependent cellular cytotoxicity. The identified ROR1 epitopes may provide a basis for generating human ROR1 MAbs for therapy. PMID:22289919

  10. Vaccinations and secondary immune thrombocytopenia with antiphospholipid antibodies by human papillomavirus vaccine.

    PubMed

    Bizjak, Mojca; Bruck, Or; Kanduc, Darja; Praprotnik, Sonja; Shoenfeld, Yehuda

    2016-04-01

    A 13-year-old girl developed immune thrombocytopenic purpura (ITP) and concomitant positive antiphospholipid antibodies (aPL) following vaccination with a quadrivalent human papillomavirus (HPV) vaccine. During the course of a disease, she developed clinical manifestation with bleeding and she was treated with intravenous immunoglobulins. Consequently, the number of her platelets remained critically low and she was put on corticosteroids and rituximab. Since then, her platelet count remain within the normal range, but her aPL are still present. PMID:27312165

  11. Human Cytokine Genetic Variants Associated With HBsAg Reverse Seroconversion in Rituximab-Treated Non-Hodgkin Lymphoma Patients

    PubMed Central

    Hsiao, Liang-Tsai; Wang, Hao-Yuan; Yang, Ching-Fen; Chiou, Tzeon-Jye; Gau, Jyh-Pyng; Yu, Yuan-Bin; Liu, Hsiao-Ling; Chang, Wen-Chun; Chen, Po-Min; Tzeng, Cheng-Hwai; Chan, Yu-Jiun; Yang, Muh-Hwa; Liu, Jin-Hwang; Huang, Yi-Hsiang

    2016-01-01

    Abstract Hepatitis B virus (HBV) reactivation has been noted in HBV surface antigen (HBsAg)-seronegative patients with CD20+ B-cell non-Hodgkin lymphoma (NHL) undergoing rituximab treatment. Clinically, hepatitis flares are usually associated with the reappearance of HBsAg (reverse seroconversion of HBsAg, HBV-RS). It is unclear whether human genetic factors are related to rituximab-associated HBV reactivation. Unvaccinated HBsAg-seronegative adults (n = 104) with CD20+ NHL who had received rituximab-containing therapy without anti-HBV prophylaxis were enrolled. Eighty-nine candidate single nucleotide polymorphisms (SNPs) of 49 human cytokine genes were chosen and were analyzed using the iPLEX technique. Competing risk regression was used to identify the factors associated with HBV-RS. Participants had a median age of 66.1 years and 56.7% were male (n = 59). The anti-HBs and anti-HBc positivity rates were 82.4% and 94.1%, respectively, among patients for whom data were available (approximately 81%). A mean of 7.14 cycles of rituximab therapy were administered, and a total of 14 (13.4%) patients developed HBV-RS. Nine SNPs showed significant differences in frequency between patients with or without HBV-RS: CD40 rs1883832, IL4 rs2243248 and rs2243263, IL13 rs1295686, IL18 rs243908, IL20 rs1518108, and TNFSF13B rs12428930 and rs12583006. Multivariate analysis showed that ≥6 cycles of rituximab therapy, IL18 rs243908, and the IL4 haplotype rs2243248∼rs2243263 were independently associated with HBV-RS. The IL4 haplotype rs2243248∼rs2243263 was significantly associated with HBV-RS regardless of anti-HBs status. Polymorphisms in human cytokine genes impact the risk of rituximab-associated HBV-RS. PMID:26986131

  12. Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis: A Randomized, Placebo-phase Trial

    PubMed Central

    Oddis, Chester V.; Reed, Ann M.; Aggarwal, Rohit; Rider, Lisa G.; Ascherman, Dana P.; Levesque, Marc C.; Barohn, Richard J.; Feldman, Brian M.; Harris-Love, Michael O.; Koontz, Diane C.; Fertig, Noreen; Kelley, Stephanie S.; Pryber, Sherrie L.; Miller, Frederick W.; Rockette, Howard E.

    2012-01-01

    Objective To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase, trial of adult and pediatric myositis. Methods Adults with refractory polymyositis and adults and children with refractory dermatomyositis were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal core set measures (CSM) for adults. JDM patients required ≥ 3 abnormal CSM with or without muscle weakness. Patients were randomized to either ‘rituximab early’ or ‘rituximab late’ and glucocorticoid and immunosuppressive therapy were allowed at entry. The primary endpoint compared the time to achieve the preliminary International Myositis Assessment and Clinical Studies Group definition of improvement (DOI) between the 2 groups. The secondary endpoints were time to achieve ≥20% improvement in muscle strength, and the proportion of early and late rituximab patients achieving DOI at week 8. Results Among 200 randomized patients (76 PM/76 DM/48 JDM), 195 showed no difference in the time to DOI between the rituximab late (n=102) and rituximab early (n=93) groups (p=0.74, log rank) with a median time to DOI of 20.2 weeks and 20.0 weeks respectively. The secondary endpoints also did not significantly differ between the two treatment groups. However, 161 (83%) of randomized patients met the DOI and individual CSM improved in both groups throughout the 44-week trial. Conclusion Although there were no significant differences in the two treatment arms for the primary and secondary endpoints, 83% of refractory adult and juvenile myositis patients met the DOI. The role of B cell depleting therapies in myositis warrants further study with consideration for a different trial design. PMID:23124935

  13. Rituximab therapy for chonic and refractory immune thrombocytopenic purpura: a long-term follow-up analysis

    PubMed Central

    Garcia-Chavez, Jaime; Montiel-Cervantes, Laura; Esparza, Miriam García-Ruiz; Vela-Ojeda, Jorge

    2007-01-01

    The aim of this study was to evaluate the long-term response to rituximab in patients with chronic and refractory immune thrombocytopenic purpura (ITP). Adults with ITP fail to respond to conventional therapies in almost 30% of cases, developing a refractory disease. Rituximab has been successfully used in these patients. We used rituximab at 375 mg/m2, IV, weekly for a total of four doses in 18 adult patients. Complete remission (CR) was considered if the platelet count was >100 × 109/l, partial remission (PR) if platelets were >50 × 109/l, minimal response (MR) if the platelet count was >30 × 109/l and <50 × 109/l, and no response if platelet count remained unchanged. Response was classified as sustained (SR) when it was stable for a minimum of 6 months. Median age was 43.5 years (range, 17 to 70). Median platelet count at baseline was 12.5 × 109/l (range, 3.0 to 26.3). CR was achieved in five patients (28%), PR in five (28%), MR in four (22%), and two patients were classified as therapeutic failures (11%). Two additional patients were lost to follow-up. The median time between rituximab therapy and response was 14 weeks (range, 4 to 32). SR was achieved in 12 patients (67%). There were no severe adverse events during rituximab therapy. During follow-up (median, 26 months; range, 12 to 59), no other immunosuppressive drugs were used. In conclusion, rituximab therapy is effective and safe in adult patients with chronic and refractory ITP. Overall response rate achieved is high, long term, and with no risk of adverse events. PMID:17874322

  14. Cytomegalovirus infection in autologous stem cell transplant recipients in the era of rituximab.

    PubMed

    Jain, Tania; John, Jisha; Kotecha, Aditya; Deol, Abhinav; Saliminia, Tanaz; Revankar, Sanjay; Chandrasekar, Pranatharthi

    2016-08-01

    The incidence of cytomegalovirus (CMV) reactivation/disease after autologous stem cell transplant (ASCT) is much lower than that after allogeneic stem cell transplantation. With the recent use of rituximab during cancer chemotherapy or conditioning regimens prior to transplantation, there has been an increasing concern of opportunistic infections including CMV. In the present study, we reviewed the patients undergoing ASCT from December 2007 to December 2013 to identify those developing CMV reactivation/disease. Out of the 978 patients who underwent ASCT at the Karmanos Cancer Institute, 239 patients were tested for symptomatic CMV reactivation based on clinical suspicion. Of the tested patients, 7/239 (2.9 %) were documented to have CMV reactivation within 90 days of ASCT. The median time to develop CMV viremia was 32 days from transplantation. Of the 239 patients tested, CMV viremia was detected in 3 out of 72 patients who received rituximab as compared to 4 out of 167 patients who did not. Three of these seven viremic patients were treated with anti-viral drugs; viremia resolved in all patients at a median of 24 days. Three patients were found to develop other bacterial and/or fungal infections following CMV viremia. Two of the seven patients died during 1-year follow-up, due to primary disease progression or Candida sepsis. None of the patients developed proven tissue-invasive CMV disease. The study did not evaluate the incidence of asymptomatic CMV infection/reactivation. Despite prior publications based on limited data, rituximab does not appear to contribute to an increased frequency of symptomatic CMV reactivation following ASCT. PMID:27225264

  15. Rituximab for the Treatment of IgG4-Related Tubulointerstitial Nephritis

    PubMed Central

    McMahon, Blaithin A.; Novick, Tessa; Scheel, Paul J.; Bagnasco, Serena; Atta, Mohamed G.

    2015-01-01

    Abstract Immunoglobulin type gamma 4 (IgG4)-related disease is a relatively newly described clinical entity characterized by a distinctive histopathological appearance, increased numbers of IgG4 positive plasma cells and often, but not always, elevated serum IgG4 concentrations. The most common renal manifestation of IgG4-related disease is tubulointerstitial nephritis marked with proteinuria, hematuria, decreased kidney function, hypocomplementemia, and radiologic abnormalities. Renal biopsy characteristics include dense lymphoplasmacytic tubulointerstitial nephritis that stains for IgG4, storiform fibrosis, and immune complex deposition in the interstitium and along tubule basement membranes. Treatment traditionally consists of prolonged glucocorticoids but cases refractory to glucocorticoids have been reported. We report a case of a 58-year-old Caucasian man who presented with fatigue, 50 pound weight loss, dyspnea, lymphadenopathy, and nephromegaly. The patient was first misdiagnosed as chronic interstitial nephritis secondary to renal sarcoid and was treated with repeated doses of prednisone. On his third relapse, he underwent a repeat renal biopsy and a diagnosis of IgG4-tubulointerstitial nephritis was confirmed. He was refractory to treatment with prednisone. The patient received Rituximab and had prompt sustained improvement in renal function. At 1 year post Rituximab treatment, his serum creatinine remains at baseline and imaging study revealed reduction in his kidney size. This is the first case report using Rituximab as a steroid sparing option for refractory IgG4-tubulointerstitial nephritis. More information is needed on the long-term effects of using of B-cell depleting agents for glucocorticoid resistant IgG4-tubulointerstitial nephritis. PMID:26266393

  16. Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjögren's syndrome: a pilot study.

    PubMed

    Alunno, A; Carubbi, F; Bistoni, O; Caterbi, S; Bartoloni, E; Di Benedetto, P; Cipriani, P; Giacomelli, R; Gerli, R

    2016-06-01

    Compelling evidence suggests that interleukin (IL)-17 and IL-17-producing cells play a pivotal role in the pathogenesis of primary Sjögren's syndrome (pSS). We investigated phenotypical and functional effects of the anti-CD20 antibody rituximab (RTX) on circulating and glandular IL-17-producing T cells in pSS. RTX is able to deplete glandular IL-17(+) CD3(+) CD4(-) CD8(-) double-negative (DN) and CD4(+) Th17 cells as well as circulating IL-17(+) DN T cells. A fraction of glandular and circulating IL-17(+) DN cells and CD4(+) T helper type 17 (Th17) cells co-expresses CD20 on the cell surface explaining, at least in part, such depletive capacity of RTX. The exposure to RTX does not rescue the in-vitro corticosteroid resistance of IL-17(+) DN T cells. Our results support further the therapeutic role in pSS of RTX that, despite its B cell specificity, appears able to also hamper IL-17-producing T cells in this disease. PMID:26814615

  17. Antibody Engineering and Therapeutics

    PubMed Central

    Almagro, Juan Carlos; Gilliland, Gary L; Breden, Felix; Scott, Jamie K; Sok, Devin; Pauthner, Matthias; Reichert, Janice M; Helguera, Gustavo; Andrabi, Raiees; Mabry, Robert; Bléry, Mathieu; Voss, James E; Laurén, Juha; Abuqayyas, Lubna; Barghorn, Stefan; Ben-Jacob, Eshel; Crowe, James E; Huston, James S; Johnston, Stephen Albert; Krauland, Eric; Lund-Johansen, Fridtjof; Marasco, Wayne A; Parren, Paul WHI; Xu, Kai Y

    2014-01-01

    The 24th Antibody Engineering & Therapeutics meeting brought together a broad range of participants who were updated on the latest advances in antibody research and development. Organized by IBC Life Sciences, the gathering is the annual meeting of The Antibody Society, which serves as the scientific sponsor. Preconference workshops on 3D modeling and delineation of clonal lineages were featured, and the conference included sessions on a wide variety of topics relevant to researchers, including systems biology; antibody deep sequencing and repertoires; the effects of antibody gene variation and usage on antibody response; directed evolution; knowledge-based design; antibodies in a complex environment; polyreactive antibodies and polyspecificity; the interface between antibody therapy and cellular immunity in cancer; antibodies in cardiometabolic medicine; antibody pharmacokinetics, distribution and off-target toxicity; optimizing antibody formats for immunotherapy; polyclonals, oligoclonals and bispecifics; antibody discovery platforms; and antibody-drug conjugates. PMID:24589717

  18. Steroid Refractory Autoimmune Haemolytic Anaemia Secondary to Sarcoidosis Successfully Treated with Rituximab and Mycophenolate Mofetil.

    PubMed

    Green, Sarah; Partridge, Erica; Idedevbo, Edore; Borg, Anton

    2016-01-01

    Autoimmune haemolytic anaemia is not a well-recognised complication of sarcoidosis. We describe the case of a 30-year-old female who presented with acute warm haemolytic anaemia and widespread lymphadenopathy. Sarcoidosis was diagnosed on lymph node biopsy and further investigation. The haemolytic anaemia responded only to a high dose of steroids. Evidence regarding treatment of steroid refractory autoimmune haemolysis secondary to sarcoidosis is lacking. Based on the emergent evidence that both disorders share common immunopathogenic mechanisms involving Th1 and Th17 lymphocytes, our patient was given rituximab and mycophenolate mofetil to successfully suppress the haemolysis and sarcoid activity. PMID:27563474

  19. Steroid Refractory Autoimmune Haemolytic Anaemia Secondary to Sarcoidosis Successfully Treated with Rituximab and Mycophenolate Mofetil

    PubMed Central

    Idedevbo, Edore; Borg, Anton

    2016-01-01

    Autoimmune haemolytic anaemia is not a well-recognised complication of sarcoidosis. We describe the case of a 30-year-old female who presented with acute warm haemolytic anaemia and widespread lymphadenopathy. Sarcoidosis was diagnosed on lymph node biopsy and further investigation. The haemolytic anaemia responded only to a high dose of steroids. Evidence regarding treatment of steroid refractory autoimmune haemolysis secondary to sarcoidosis is lacking. Based on the emergent evidence that both disorders share common immunopathogenic mechanisms involving Th1 and Th17 lymphocytes, our patient was given rituximab and mycophenolate mofetil to successfully suppress the haemolysis and sarcoid activity. PMID:27563474

  20. Activity and safety of combined rituximab with chlorambucil in patients with mantle cell lymphoma.

    PubMed

    Bauwens, Deborah; Maerevoet, Marie; Michaux, Lucienne; Théate, Ivan; Hagemeijer, Anne; Stul, Michel; Danse, Etienne; Costantini, Sabrina; Vannuffel, Pascal; Straetmans, Nicole; Vekemans, Marie-Christiane; Deneys, Véronique; Ferrant, Augustin; Van Den Neste, Eric

    2005-11-01

    We evaluated the combination of rituximab with chlorambucil in patients with mantle cell lymphoma (MCL) not eligible for aggressive therapy. Fourteen patients (male/female: 9/5) were included (two newly diagnosed, 12 relapsed/refractory). The toxicities were neutropenia, thrombopenia and infection. Nine (64%) patients responded; five (36%) achieved complete remission and four (29%) achieved partial remission. The median progression-free survival for responders was 26 months (95% CI, 4-48). Marrow polymerase chain reaction negativity was attained in seven responders. These results suggest that this schedule may have notable antitumour activity in patients with MCL, including patients in relapse after autologous stem cell transplantation. PMID:16225653

  1. Consensus statement on the use of rituximab in patients with rheumatoid arthritis

    PubMed Central

    Smolen, J S; Keystone, E C; Emery, P; Breedveld, F C; Betteridge, N; Burmester, G R; Dougados, M; Ferraccioli, G; Jaeger, U; Klareskog, L; Kvien, T K; Martin‐Mola, E; Pavelka, K

    2007-01-01

    A large number of experts experienced in the treatment of rheumatoid arthritis were involved in formulating a consensus statement on the use of B cell‐targeted treatment with rituximab in patients with rheumatoid arthritis. The statement was supported by data from randomised controlled clinical trials and the substantial literature on oncology. The statement underwent three rounds of discussions until its ultimate formulation. It should guide clinicians in the use of this newly approved biological agent in treating patients with rheumatoid arthritis. PMID:17068064

  2. In vitro and in vivo evaluation of novel ligands for radioimmunotherapy.

    PubMed

    Chong, Hyun-Soon; Milenic, Diane E; Garmestani, Kayhan; Brady, Erik D; Arora, Hans; Pfiester, Candice; Brechbiel, Martin W

    2006-05-01

    Novel ligands cis-2,6-bis[N,N-bis(carboxymethyl)aminomethyl]-1-piperidineacetic acid (PIP-DTPA), cis-[(1R,11S)-6,9,15-Tris-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadec-3-yl]-acetic acid (PIP-DOTA), cis-{2,7-bis-[bis-carboxymethyl-amino)-methyl]-azepan-1-yl}-acetic acid (AZEP-DTPA), [2-(4,7-bis-carboxymethyl-[1,4,7]triazacyclononan-1-yl-ethyl]-2-carbonylmethyl-amino]-tetraacetic acid (NETA) and [{4-carboxymethyl-7-[2-(carboxymethylamino)-ethyl]-perhydro-1,4,7-triazonin-1-yl}-acetic acid (NPTA) are investigated as potential chelators of 177Lu, 90Y, 212Pb and 213Bi for radioimmunotherapy (RIT). The new ligands are radiolabeled with 177Lu, 86/88/90Y, 203Pb and 205/6Bi, and in vitro stability and in vivo stability of the radiolabeled complexes are assessed in human serum and athymic mice, respectively. In vitro studies indicate that all radiolabeled complexes with the exception of 90Y-AZEP-DTPA are stable in serum for 5-11 days. All new ligands examined herein are found to tightly hold 177Lu in vivo. Piperidine-backboned DTPA (PIP-DTPA) complexes radiolabeled with all radioisotopes examined display excellent in vivo stability, that is, excretion without dissociation. The azepane-backboned DTPA derivative, AZEP-DTPA, appears ineffective in binding all but 177Lu in vivo. NETA and NPTA radiolabeled with 86Y or 177Lu exhibit rapid blood clearance and low organ uptakes. Significant accretion in the kidney, femur and/or liver is observed with 203Pb-labeled AZEP-DTPA, PIP-DOTA and NPTA. Both 203Pb-PIP-DOTA and 205/6Bi-PIP-DOTA result in moderate to high renal accumulation of radioactivity. NETA exhibits improved renal accumulation with respect to PIP-DOTA for 205/6Bi but also shows significant liver uptake. Of all ligands studied, only PIP-DTPA appears to effectively bind 203Pb and 205/6Bi in vivo. PIP-DTPA, PIP-DOTA, NETA and NPTA all show strong evidence of rapid blood clearance and low organ uptake for 177Lu and 90Y. Serum stability and in vivo biodistribution

  3. Comparative efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    DOE PAGESBeta

    Frost, Sofia H. L.; Frayo, Shani L.; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark D.; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; et al

    2015-03-18

    Purpose Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targetingmore » either 90Y or 177Lu to human B-cell lymphoma xenografts in mice. Methods Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibodystreptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. Results The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTAbiotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes. Conclusion 90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT

  4. [Monoclonal antibodies for the treatment of multiple sclerosis].

    PubMed

    Sánchez-Seco, Victoria Galán; Casanova Peño, Ignacio; Arroyo González, Rafael

    2014-12-01

    Until the mid 1990s, with the appearance of interferon beta and glatiramer acetate, there was no treatment for multiple sclerosis (MS). However, due to their moderate therapeutic potential in some patients, a broad search was continued to find new and more effective treatment strategies, largely concentrated on monoclonal antibodies (MOAB). Natalizumab, the first MOAB for the treatment of MS, was approved at the end of 2004, representing a major advance in the field of neuroimmunology. Today, there is broad experience with natalizumab and other MOAB (alemtuzumab, daclizumab, rituximab, ocrelizumab, ofatumumab and anti-lingo-1) that are pending commercialization or are under phase II or III of development with promising results. The present review analyzes the efficacy and safety results of all these drugs. PMID:25732947

  5. Synthesis of Lutetium Phosphate/Apoferritin Core-Shell Nanoparticles for Potential Applications in Radioimmunoimaging and Radioimmunotherapy of Cancers

    SciTech Connect

    Wu, Hong; Engelhard, Mark H.; Wang, Jun; Fisher, Darrell R.; Lin, Yuehe

    2008-04-01

    We report a novel approach for synthesizing LuPO4/apoferritin core-shell nanoparticles based on an apoferritin template, conjugated to the protein biotin. To prepare the nanoparticle conjugates, we used non-radioactive lutetium as a model target or surrogate for radiolutetium (177Lu). The central cavity, multi-channel structure, and chemical properties of apoferritin are well-suited for sequentially diffusing lutetium and phosphate ions into the cavity--resulting in a stable core-shell composite. We characterized the synthesized LuPO4/apoferritin nanoparticle using transmission electron microscopy (TEM) and x-ray photoelectron spectroscopy (XPS). We tested the pre-targeting capability of biotin-modified lutetium/apoferritin nanoparticle using streptavidin-modified magnetic beads and streptavidin-modified fluorescein isothiocyanate (FITC) tracer. This paper presents a simple, fast, and efficient method for synthesizing LuPO4/apoferritin nanoparticle conjugates with biotin for potential applications in radioimmunotherapy and radioimmunoimaging of cancer.

  6. Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease.

    PubMed

    Uldrick, Thomas S; Polizzotto, Mark N; Aleman, Karen; Wyvill, Kathleen M; Marshall, Vickie; Whitby, Denise; Wang, Victoria; Pittaluga, Stefania; O'Mahony, Deirdre; Steinberg, Seth M; Little, Richard F; Yarchoan, Robert

    2014-12-01

    Kaposi sarcoma (KS) herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a lymphoproliferative disorder, most commonly seen in HIV-infected patients, that has a high mortality if untreated. Concurrent KS is common. Although rituximab has reported activity in KSHV-MCD, its use is often associated with KS progression. Within a natural history study of KSHV-MCD, we prospectively evaluated rituximab 375 mg/m(2) combined with liposomal doxorubicin 20 mg/m(2) (R-Dox) every 3 weeks in 17 patients. Patients received a median of 4 cycles (range 3-9). All received antiretroviral therapy, 11 received consolidation interferon-α, and 6 received consolidation high-dose zidovudine with valganciclovir. Using NCI KSHV-MCD response criteria, major clinical and biochemical responses were attained in 94% and 88% of patients, respectively. With a median 58 months' potential follow-up, 3-year event-free survival was 69% and 3-year overall survival was 81%. During R-Dox therapy, cutaneous KS developed in 1 patient, whereas 5 of 6 patients with it had clinical improvement. R-Dox was associated with significant improvement in anemia and hypoalbuminemia. KSHV viral load, KSHV viral interleukin-6, C-reactive protein, human interleukin-6, and serum immunoglobulin free light chains decreased with therapy. R-Dox is effective in symptomatic KSHV-MCD and may be useful in patients with concurrent KS. This trial was registered at www.clinicaltrials.gov as #NCT00092222. PMID:25331113

  7. Rituximab in the treatment of diffuse large B-cell lymphoma primary of the lung.

    PubMed

    Aviles, Agustin; Nambo, Maria J; Huerta-Guzman, Judith; Silva, Luis; Neri, Natividad

    2013-03-01

    Diffuse large B-cell lymphoma primary of lung (DLBCL-PL) is a rare presentation of extranodal lymphoma, in most cases chemotherapy-based anthracyclines: CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the treatment, with excellent outcome. The addition of rituximab to CHOP (R-CHOP) has been considered the gold standard in the treatment of nodal DLBCL. Thus, we assess in a large number of cases of DLBCL-PL whether the use of R-CHOP could improve survival in this setting of patients. Forty-two patients with DLBCL-PL, stage IE, age 65 years or younger, were treated with standard R-CHOP, no consolidation radiotherapy or maintenance therapy were considered. They were matched with patients who received CHOP alone to assess efficacy and toxicity. Complete response was observed in 35 patients (83%), and 7 patients were considered failure (16%). The study has a median follow-up of 42.8 months. Actuarial curves at 5 years showed that progression-free survival was 88 % and overall survival was 70 %. The results were not statistically different when compared retrospectively with patients who received CHOP alone. Treatment was well tolerated. The addition of rituximab to chemotherapy did not improve outcome in patients with DLBCL-PL. PMID:23394581

  8. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy

    PubMed Central

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou–Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies. PMID:27579294

  9. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia

    PubMed Central

    Mahévas, Matthieu; Lee, Soo Y.; Stasi, Roberto; Cunningham-Rundles, Susanna; Godeau, Bertrand; Kanter, Julie; Neufeld, Ellis; Taube, Tillmann; Ramenghi, Ugo; Shenoy, Shalini; Ward, Mary J.; Mihatov, Nino; Patel, Vinay L.; Bierling, Philippe; Lesser, Martin; Cooper, Nichola; Bussel, James B.

    2012-01-01

    Treatments for immune thrombocytopenic purpura (ITP) providing durable platelet responses without continued dosing are limited. Whereas complete responses (CRs) to B-cell depletion in ITP usually last for 1 year in adults, partial responses (PRs) are less durable. Comparable data do not exist for children and 5-year outcomes are unavailable. Patients with ITP treated with rituximab who achieved CRs and PRs (platelets > 150 × 109/L or 50-150 × 109/L, respectively) were selected to be assessed for duration of their response; 72 adults whose response lasted at least 1 year and 66 children with response of any duration were included. Patients had baseline platelet counts < 30 × 109/L; 95% had ITP of > 6 months in duration. Adults and children each had initial overall response rates of 57% and similar 5-year estimates of persisting response (21% and 26%, respectively). Children did not relapse after 2 years from initial treatment whereas adults did. Initial CR and prolonged B-cell depletion predicted sustained responses whereas prior splenectomy, age, sex, and duration of ITP did not. No novel or substantial long-term clinical toxicity was observed. In summary, 21% to 26% of adults and children with chronic ITP treated with standard-dose rituximab maintained a treatment-free response for at least 5 years without major toxicity. These results can inform clinical decision-making. PMID:22566601

  10. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy.

    PubMed

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignanc