This article reports the affibody-based nanoprobes specifically target and image human epidermal growth factor receptor type 2 (HER2)-expressing cells and tumors. The affibody molecules are a promising class of targeting ligands with simple, robust, and precise structure and high affinity. Using near-infrared (NIR) quantum dots (QDs) and iron oxide (IO) ...
PubMed
... Accession Number : ADA381281. Title : Anti-HER2/Toxin Expressing Lymphocytes for Breast Cancer Therapy. Descriptive Note : Annual rept. ...
DTIC Science & Technology
... MEDICINE, NEOPLASMS, PENETRATION, TARGETING, SURGERY, ANTIGENS, ALPHA PARTICLES, DOSIMETRY, NORMALITY, INFUSIONS. ...
A novel delivery carrier was developed using artificial oil bodies (AOBs). Plant seed oil bodies (OBs) consist of a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with the storage protein oleosin (Ole). Ole consists of a central hydrophobic domain with two amphiphatic arms that extrude from the surface of OBs. In this study, a bivalent ...
NASA Astrophysics Data System (ADS)
... Abstract : We have found myeloid-derived suppressor cells (MDSC) to be the major inhibitors of adoptively transferred anti-HER2/neu T cells in vivo ...
... Corporate Author : UNIVERSITY OF MEDICINE AND DENTISTRY OFNEW JERSEY ... to a short "anchor" 2'-0-methyl RNA complementary to non ...
... MAMMALS, NEOPLASMS, IN VITRO ANALYSIS, THERAPY, PATIENTS, RESPONSE(BIOLOGY), CELLS(BIOLOGY), LYMPHOCYTES, DISEASE ...
In our laboratory we have developed lentiviral vectors for use in anti-breast cancer gene therapy. Our specific goal for this project was to evaluate the feasibility of using lentiviral vectors that express anti-HER-2/neu antisense or ribozymes for the tr...
National Technical Information Service (NTIS)
In our laboratory we have developed lentiviral vectors for use in anti-breast cancer gene therapy. Our specific goal for this project is to evaluate the feasibility of using lentiviral vectors that express anti-HER-2/neu antisense or ribozymes for the tre...
Age Race Stage of disease Nodal involvement Hormone receptor status Buzdar A, et al. Buzdar A, et al. Clin Clin Cancer Res. Cancer Res.
Cancer.gov
The goal of the first phase of this project, which constitutes the major technological challenge to be overcome, is to design a peptide compound capable of binding to HER-2/neu RNA in the presence of a large excess of unrelated RNA. To accomplish this goa...
Cyclin E is a key regulator of the mammalian cell cycle, as it is rate limiting for progression from G1 to S phase. Deranged cyclin E expression has been found both quantitatively (overexpression) and qualitatively (multiple isoforms) in almost all breast...
Tumor necrosis factor (TNF)-alpha genetically fused to the carboxyl terminus of a single-chain Fv (ScFv) antibody specific for the human HER2/neu (anti-HER2/neu ScFv-TNF-alpha) forms a homotrimeric structure that retains both TNF-alpha activity and the ability to bind HER2/neu. In contrast to anti-HER2/neu IgG3, ...
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pancr�as Combination of anti-EGFR and anti-HER2 antibodies : hope in pancreatic cancer treatment 1 Christel, cancer, pancr�as Abstract. Unresectable pancreatic cancer is still an extremely dismal prognosis and HER2 have been reported to be implicated and upregulated in pancreatic cancer tumorigenesis. The use
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long term immune surveillance thus avoiding or delaying the onset of recurrence. Recently, Benavides et-overexpressing tumors, different studies have shown cellular and/or humoral immune responses against HER2 to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2
Affibody molecules constitute a novel class of molecular display selected affinity proteins based on non-immunoglobulin scaffold. Preclinical investigations and pilot clinical data have demonstrated that Affibody molecules provide high contrast imaging of tumor-associated molecular targets shortly after injection. The use of cysteine-containing ...
... Bioconjugated gold (Au) nanoparticle (NP) imaging ... with PEG and an anti-Her2 neu affibody, we were able to create nanoparticles which were ...
177Lu-CHX-A''-DTPA-ABD-Affibody (ZHER2:342)2 [177Lu-ABD-(ZHER2:342)2] Huiming Zhang, PhD National Lu-CHX-A''-DTPA-ABD-Affibody (ZHER2:342)2 Abbreviated name: 177 Lu-ABD-(ZHER2:342)2 Synonym: Agent a peptide/protein effector function (6). 177Lu-CHX-A''-DTPA-ABD-Affibody (ZHER2:342)2 (177Lu-ABD-(ZHER2
The goal of this investigation was to develop stable radioimmunoconjugates (RICs) of anti-HER2/neu monoclonal antibodies (MoAbs) for imaging and therapy in an animal model bearing human breast tumor xenografts that express normal (MCF-7 cells) and increased amounts of HER2/neu receptors (HCC-1954, BT-474, SKBR-3 cells) on their cell surface membranes. Pharmacy-grade Herceptin, a murine ...
The aggregation of amyloid-? (A?) peptides is believed to be a major factor in the onset and progression of Alzheimer's disease. Molecules binding with high affinity and selectivity to A?-peptides are important tools for investigating the aggregation process. An A?-binding Affibody molecule, ZA?3 , has earlier been selected by phage display and shown to bind A?(1-40) with ...
The presence of human epidermal growth factor type 2 (HER2) on 20�30% of human breast cancer is a prognostic indicator of more rapid disease progression and a therapeutic indicator for anti-HER2 monoclonal antibodies. Because the literature has demonstrated some discordance between primary and metastatic tumors in the same patient for expression of the HER2 marker, we set out to develop an ...
PubMed Central
The antiangiogenic protein endostatin showed considerable preclinical antitumor activity, but limited efficacy in phase I/II trials. Prior studies using an anti-HER2 antibody-murine endostatin fusion showed enhanced antitumor activity compared to anti-HER2 antibody or endostatin given alone, or in combination. We have generated two anti-HER2 human ...
A suggestive case of metastatic disease from breast cancer is reported. The HER-2-positive tumor was refractory to several agents, including anti-HER-2 therapy, trastuzumab, and lapatinib. After re-induction of trastuzumab in combination with activated natural killer (NK) cell injection therapy, tumor markers decreased, and finally a synergistic effect of ...
The PI3K/PTEN pathway plays a major role in carcinogenesis. Dysregulation of this pathway occurs frequently in breast cancer, and loss of PTEN expression is emerging as a potentially important mechanism of resistance to the widely used anti-HER2 therapy, trastuzumab. However, assays for loss of PTEN expression have suffered from lack of consistency. Here, ...
(10� 12). Biodistribution studies in SCID mice with various anti- HER-2 (13) and anti-CEA5 (14-44-635-5570; Fax: 41-44-635-5712; E-mail: plueckthun@bioc.unizh.ch. 5 The abbreviations used are: CEA, polyethylene gly- col; RIA, radioimmunoassay; RU, resonance units; scFv, single chain Fv frag- ment; MES, 4
111In-Diethylenetriaminepentaacetic acid-trastuzumab [111In-DTPA-humAb4D5-8] Kenneth T. Cheng, Ph: 111 In-Diethylenetriaminepentaacetic acid-trastuzumab Abbreviated name: 111 In-DTPA-humAb4D5-8 Synonym: 111 In-Herceptin� , 111 In-anti-HER2 MAb, 111 In-DTPA-trastuzumab. Agent Category: Antibody Target
Affibody molecules are a new class of small targeting proteins based on a common three-helix bundle structure. Affibody molecules binding a desired target may be selected using phage-display technology. An Affibody molecule Z HER2:342 binding with subnanomolar affinity to the tumor antigen HER2 has recently been developed for ...
Breast cancer is a widely spread women's disease. In spite of progress in the field of surgery and adjuvant therapies, the risk of breast cancer metastatic relapses remains high especially in those overexpressing HER2. Different studies have shown cellular and/or humoral immune responses against HER2 in patients with HER2-overexpressing tumors. This immune response is associated with a lower tumor ...
Anti-HER2 antibody conjugated with quantum dots (anti-HER2ab-QDs) is a very recent fluorescent nanoprobe for HER2+ve breast cancer imaging. In this study we investigated in-vivo toxicity of anti-HER2ab conjugated CdSe/ZnS QDs in Wistar rats. For toxicity evaluation of injected QDs sample, body weight, organ ...
Each year, breast cancer accounts for more than 400,000 new cancer cases and more than 130,000 cancer deaths in Europe. Prognosis of nonmetastatic breast cancer patients is directly related to the extent of the disease, mainly nodal spreading and tumor size, and to the molecular profile, particularly HER2 over-expression. In patients with HER2-over-expressing tumors, different studies have shown ...
Each year, breast cancer accounts for more than 400.000 new cancer cases and more than 130.000 cancer deaths in Europe. Prognosis of non metastatic breast cancer patients is directly related to extend of the disease, mainly nodal spreading and tumor size, and to molecular profile, particularly HER2 overexpression. In patients with HER2-overexpressing tumors, different studies have shown cellular ...
Thermosensitive liposomes are attractive vehicles for the delivery and release of drugs to tumors. To improvethe targeting efficacy for breast cancer treatment, an 8.3-kDa HER2-specific Affibody molecule (Z(HER2:342)-Cys) was conjugated to the surface of liposomes. The effects of this modification on physical characteristics and stability of the resulting nanoparticles denoted ...
111In-CHX-A"-diethylenepentaacetic acid-Affibody ZHER2:2395-Cys [111In-CHX-A''-DTPA-Z2395-C] Kam: 111 In-CHX-A"-diethylenepentaacetic acid-Affibody ZHER2:2395-Cys Abbreviated name: 111 In-CHX-(2,5-dioxo-2,5-dihydro-pyrrol-1-ul)-heptanoylamino]-phenyl}-propyl)-amino]-acetic acid (maleimido-CHX
, also known as erbitux and cetuximab) was labeled as 99mTc-EC- C225 (22, 23) to image EGFR expression in OMIM � Clinical trials (Trastuzumab, cetuximab) � Drug information in FDA (Trastuzumab, cetuximab
Affibody molecules are non-immunoglobulin-derived affinity proteins based on a three-helical bundle protein domain. Here, we describe the design process of an optimized Affibody molecule scaffold with improved properties and a surface distinctly different from that of the parental scaffold. The improvement was achieved by applying an iterative process of ...
Abstract The overexpression of the epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC) is associated with poor prognosis. Targeted nuclear imaging of the EGFR expression could improve the diagnostics in patients with HNSCC. However, the high expression of EGFR in normal organs may conceal the tumor uptake and therefore limit the use. This study assesses the ...
Affibody molecules are a new class of small phage-display selected proteins using a scaffold domain of the bacterial receptor protein A. They can be selected for specific binding to a large variety of protein targets. An affibody molecule binding with high affinity to a tumor antigen HER2 was recently developed for radionuclide diagnostics and therapy in ...
Platelet-derived growth factor receptor (PDGFR) ? is a marker of stromal pericytes and fibroblasts and represents an interesting target for both diagnosis and therapy of solid tumors. A receptor-specific imaging agent would be a useful tool for further understanding the prognostic role of this receptor in vivo. Affibody molecules constitute a class of very small binding ...
Affibody molecules have received significant attention in the fields of molecular imaging and drug development. However, Affibody scaffolds display an extremely high renal uptake, especially when modified with chelators and then labeled with radiometals. This unfavorable property may impact their use as radiotherapeutic agents in general and as imaging ...
Affibody molecules are a new class of small targeting proteins based on a common threehelix bundle structure. Affibody molecules binding a desired target may be selected using phage-display technology. An Affibody molecule ZHER2:342 binding with subnanomolar affinity to the tumor antigen HER2 has recently been ...
A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal ...
The present work demonstrates the use of small bivalent engineered antibody fragments, cys-diabodies, for biological modification of nanoscale particles such as quantum dots (Qdots) for detection of target antigens. Novel bioconjugated quantum dots known as immunoQdots (iQdots) were developed by thiol-specific oriented coupling of tumor specific cys-diabodies, at a position away from the antigen ...
The present work demonstrates the use of small bivalent engineered antibody fragments, cys-diabodies, for biological modification of nanoscale particles such as Quantum dots (Qdots) for detection of target antigens. Novel bioconjugated quantum dots known as immunoQdots (iQdots) were developed by thiol-specific oriented coupling of tumor specific cys-diabodies, at a position away from the antigen ...
A 4-component antibody-phthalocyanine-polyethylene glycol-gold nanoparticle conjugate is described for use as a potential drug for targeted photodynamic cancer therapy. Gold nanoparticles (4 nm) were stabilised with a self-assembled layer of a zinc-phthalocyanine derivative (photosensitiser) and a heterobifunctional polyethylene glycol. Anti-HER2 ...
We report a strategy for the generation of heterodimeric protein conjugates using an unnatural amino acid with orthogonal reactivity. This paper addresses the challenges of site-specificity and homogeneity with respect to the synthesis of bivalent proteins and antibody-drug conjugates. There are numerous antibody-drug conjugates in preclinical and clinical development, yet these are based either ...
Affibody protein is an engineered protein scaffold with a three-helical bundle structure. Affibody molecules of small size (7 kD) have great potential for targeting overexpressed cancer biomarkers in vivo. To develop an Affibody-based molecular probe for in vivo optical imaging of epidermal growth factor receptor (EGFR) positive ...
A hyperbranched conjugated polyelectrolyte (HCPE) with a core-shell structure is designed and synthesized via alkyne polycyclotrimerization and click chemistry. The HCPE has an emission maximum at 565 nm with a quantum yield of 12% and a large Stokes shift of 143 nm in water. By virtue of its poly(ethylene glycol) shell, this polymer naturally forms spherical nanoparticles that minimize ...
There are four members of the ErbB family: the epidermal growth factor(EGF)receptor(also called HER1 or EGFR), HER2, HER3 and HER4. Dimerization is the process whereby two HER receptor molecules associate to form a noncovalent complex. HER dimers are the active receptor forms required for transmission of external stimuli to the interior of the cell. HER dimerization occurs upon ligand binding and ...
Trastuzumab is a FDA-approved drug that has shown clinical efficacy against HER2+ breast cancers and is commonly used in combination with other chemotherapeutics. However, many patients are innately resistant to trastuzumab, or will develop resistance during treatment. Alternative treatments are needed for trastuzumab-resistant patients. Here, we investigate gold nanoparticle-mediated photothermal ...
The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor overexpressed in 30% of human breast cancers. One of the mechanisms by which tumor cell proliferation can be inhibited consists in hampering HER2 dimerization by targeting its extracellular domain with specific antibodies. In recent clinical practice, a valuable alternative to entire IgGs resides in the ...
Prospective studies have demonstrated that approximately 20% of HER2 testing may be inaccurate. When carefully validated testing is conducted, available data do not clearly demonstrate the superiority of either IHC or fluorescence in situ hybridization (FISH) as a predictor of benefit from anti-HER2 therapy. In addition, the interpretation of the findings ...
Approximately one quarter of patients with breast cancer demonstrate amplification of the human epidermal receptor type 2 (HER2) gene, the expression of which is associated with a relatively poor prognosis independent of other clinical and pathologic variables. Trastuzumab, a humanized recombinant monoclonal antibody specifically directed against the HER2 receptor, has been shown to be ...
The affibody functionalization of fluorescent surface-enhanced Raman scattering gold-silica nanoparticles as multimodal contrast agents for molecular imaging specific to epidermal growth factor receptor (EGFR) is reported. This nanoparticle bioconjugate reports EGFR-positive A431 tumors with a signal nearly 35-fold higher than EGFR-negative MDA-435S tumors. The low-level EGFR ...
.biotech.kth.se KTH School of Biotechnology Department of Molecular Biotechnology Affibody binding proteins. The small three-helix bundle protein (58 aa) is subjected to genetic randomization corresponding to 13 surface targets can be isolated and identified by appropriate selection methods. Head of Department: Prof. Per
Expression of receptor tyrosine-kinase (RTK) EGFR is low in normal prostate, but increases in prostate cancer. This receptor is significantly up-regulated as tumors progress into higher grade, androgen-insensitive and metastatic lesions. The up-regulated receptors could serve as targets for novel selective anti-cancer drugs, e.g. antibodies and tyrosine kinase inhibitors. Radionuclide imaging of ...
HER2-specific affibody molecules in different formats have previously been shown to be useful tumor targeting agents for radionuclide-based imaging and therapy applications, but their biological effect on tumor cells is not well known. In this study, two dimeric ((Z{sub HER2:4}){sub 2} and (Z{sub HER2:342}){sub 2}) and one monomeric (Z{sub HER2:342}) HER2-specific ...
Energy Citations Database
or a mutated transmembrane epidermal growth factor receptor (EGFR; for details regarding this receptor family imaging) or treatment of cancers that are known to involve the EGFR includes the use of anti-EGFR protein A, is directed against the human EGFR2 (HER2) and has been investigated extensively (5). The non
Nano-materials are expected for research on molecular imaging of pharmacokinetics. We measured in vivo migration of CdSe nano-particles(Quantum Dots(QDs))conjugated with monoclonal anti-HER2 antibody(trastuzumab)in tumor vessel to breast cancer cells. We established a high resolution in vivo 3D microscopic system for a novel imaging method at single ...
Antitumor activity of molecules and cells of the innate immune system has been reported. Here we propose a method for targeting preferred innate immune cells and magnifying their tumoricidal effect at the tumor microenvironment, by modular multiple-component complexes (termed TILTAN). As a model, micro-scale complexes were assembled carrying monoclonal ...
We show that single walled carbon nanotubes (SWNTs) with different isotope compositions exhibit distinct Raman G-band peaks and can be used for multiplexed multicolor Raman imaging of biological systems. Cancer cells with specific receptors are selectively labeled with three differently "colored" SWNTs conjugated with various targeting ligands including Herceptin ...
Herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2 (HER2), was covalently attached to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. The specific binding and internalization of this conjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2 by flow cytometry as well as confocal ...
Herceptin a humanized monoclonal antibody that binds to human growth factor receptor-2 (HER2) was covalently attached to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. The specific binding and internalization of this conjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2 by flow cytometry as well as confocal microscopic ...
In this study, we report the fabrication of engineered iron oxide magnetic nanoparticles (MNPs) functionalized with anti-human epidermal growth factor receptor type 2 (HER2) antibody to target the tumor antigen HER2. The Fc-directed conjugation of antibodies to the MNPs aids their efficient immunospecific targeting through free Fab portions. The directional specificity of conjugation was verified ...
Advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. In North America, about 70% of cases are advanced or metastatic when diagnosed, which is higher than the 50% reported in Japan. This difference in presentation is reflected in 5-year overall survival, which is about 20% in North America and 40%�60% in Japan. Despite numerous efforts of randomized ...
Gold nanocages with an average edge length of 65 � 7 nm and a strong absorption peak at 800 nm were conjugated with monoclonal antibodies (anti-HER2) to target breast cancer cells (SK-BR-3) through the epidermal growth factor receptor (in this case, HER2), which is overexpressed on the surfaces of the cells. Both the number of immuno Au nanocages ...
BACKGROUND: Continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone in women with HER2-positive breast cancer progressing during trastuzumab treatment. Here, we report the final analysis on overall survival. PATIENTS AND METHODS: Patients with HER2-positive, advanced breast cancer who ...
BackgroundEsophageal adenocarcinoma (EAC) is a highly aggressive disease with poor prognosis, which frequently exhibits HER-2 gene amplification. Trastuzumab, the humanized antibody against HER-2, has potent growth inhibitory effects on HER-2 overexpressing cancers. One effect of trastuzumab is that it causes HER-2 receptor internalization and degradation, enhancing presentation of HER-2 epitopes ...
In oncology, simultaneous inhibition of epidermal growth factor receptor (EGFR) and HER2 by monoclonal antibodies (mAbs) is an efficient therapeutic strategy but the underlying mechanisms are not fully understood. Here, we describe a time-resolved fluorescence resonance energy transfer (TR-FRET) method to quantify EGFR/HER2 heterodimers on cell surface to shed some light on the mechanism of such ...
NKG2D ligands link the innate and adapative immune response by activating the receptors expressed on effector cells of both the innate (NK) and adaptive immune systems (CD8(+) T cells). In this study, we explored the potential therapeutic utility of this intersection by fusing the murine NKG2D ligand Rae-1? to the 3' end of an anti-HER2 IgG3 antibody containing an intact Fc domain ...
Targeting of non-phagocytic tumor cells and prompt release of gene cargos upon entry into tumors are two limiting steps in the bacterial gene delivery path. To tackle these problems, the non-pathogenic Escherichia coli strain BL21(DE3) was engineered to display the anti-HER2/neu affibody on the surface. After co-incubation with tumor cells for 3 h, the anti-HER2/neu ...
We have optimized the display of the B domain of staphylococcal protein A on the surface of Lactococcus lactis. The maximum binding capacity was estimated at 0.146 ?g of antibody per 108 cells and was sustained at 86% after treatment with simulated gastric juice. A tumor necrosis factor alpha (TNF-?)-binding affibody was also displayed and bound TNF-?, ...
INTRODUCTION: The development of molecular probes based on novel engineered protein constructs is under active investigation due to the great potential of this generalizable strategy for imaging a variety of tumor targets. DISCUSSION: In this report, human epidermal growth factor receptor type 2 (HER2)-binding Affibody molecules were radiolabeled with (64)Cu and their imaging ...
The human epidermal growth factor receptor HER2 has emerged as an important target for molecular imaging of breast cancer. This article presents the design and synthesis of a HER2-targeting affibody molecule with improved stability and tumor targeting capacity, and with potential use as an imaging agent. The 58 aa three-helix bundle protein was assembled using solid-phase ...
ABSTRACT: INTRODUCTION: Novel adjuvant therapies are needed to prevent metastatic relapses in HER2-expressing breast cancer. Here, we tested whether trastuzumab-selected single-chain Fv (scFv) could be used to develop an anti-idiotype-based vaccine to inhibit growth of HER2-positive tumor cells in vitro and in vivo through induction of long-lasting HER-specific immunity. METHODS: BALB/c mice were ...
IntroductionNovel adjuvant therapies are needed to prevent metastatic relapses in HER2-expressing breast cancer. Here, we tested whether trastuzumab-selected single-chain Fv (scFv) could be used to develop an anti-idiotype-based vaccine to inhibit growth of HER2-positive tumor cells in vitro and in vivo through induction of long-lasting HER-specific immunity.MethodsBALB/c mice were immunized with ...
The development of targeted and triggerable delivery systems is of high relevance for anticancer therapies. We report here on reduction-sensitive liposomes composed of a novel multifunctional lipidlike conjugate, containing a disulfide bond and a biotin moiety, and natural phospholipids. The incorporation of the disulfide conjugate into vesicles and the kinetics of their reduction were studied ...
Imaging and local therapy are important modalities for detection and management of localized breast cancer. Improvements in screening and local therapy have contributed to reduced breast cancer-associated morbidity and mortality. The Coalition of Cancer Cooperative Groups (CCCG) convened the Scientific Leadership Council (SLC) in breast cancer, an expert panel, to identify priorities for future ...
Exosomes are endosome-derived nanovesicles actively released into the extracellular environment and biological fluids, both under physiological and pathological conditions, by different cell types. We characterized exosomes constitutively secreted by HER2-overexpressing breast carcinoma cell lines and analyzed in vitro and in vivo their potential role in interfering with the therapeutic activity ...
Breast cancer is the most common cancer among women and it is the second leading cause of cancer deaths in women today. The key to the effective and ultimately successful treatment of diseases such as cancer is an early and accurate diagnosis. Driven by the need, in this article, we report for the first time a simple colorimetric and highly sensitive two-photon scattering assay for highly ...
Twenty percent of breast cancer adenocarcinomas overexpress the oncogene c-erb-2 that is recognized by the humanized anti-Her2/neu monoclonal antibody Herceptin. Results from clinical studies suggest that antibody-dependent cellular cytotoxicity (ADCC) is involved in the clinical response of Herceptin-treated patients. The purpose of the current study was ...
The Her-2/neu oncogene is overexpressed in approximately 30% of breast and ovarian cancer cases and often indicates a poor prognosis. Therapeutic agents against Her-2/neu have been intensively sought over the past decade. Here we show that small interfering RNA (siRNA) can silence the expression of Her-2/neu in models of human breast or ovarian cancer through retrovirus-mediated transfer of an ...
BACKGROUND: Circulating tumor cells (CTCs) are a prognostic marker in metastatic breast cancer, but comparisons with serum tumor markers (CA 15-3, carcinoembryonic antigen and lactate dehydrogenase) variations are needed. PATIENTS AND METHODS: CTCs were counted with CellSearch� at baseline, before cycle 2 (C2) and cycle 3 or 4 (C3/4) in 267 metastatic breast cancer patients on first-line ...
Trastuzumab has changed the prognosis of HER2 positive breast cancers. Despite this progress, resistance to trastuzumab occurs in most patients. Newer anti-HER2 therapies, like the dual tyrosine-kinase inhibitor (TKI) lapatinib, show significant antitumor activity, indicating that HER2 can be still exploited as a target after trastuzumab failure. However, ...
AimsHER2 gene amplification has been detected in 10�20% of gastric adenocarcinomas. In view of the recently demonstrated clinical benefit of the anti-human epidermal growth factor receptor 2 (HER2) drug trastuzumab in the treatment of advanced gastric cancer, reliable HER2 testing is of key importance. The aim of this study was to examine HER2 status in gastro-oesophageal adenocarcinomas ...
Amplification and overexpression of the HER-2 oncogene in breast cancer is felt to be stable over the course of disease and concordant between primary tumor and metastases. Therefore, patients with HER-2-negative primary tumors rarely will receive anti-Her-2 antibody (trastuzumab, Herceptin) therapy. A very sensitive blood test was used to capture ...
A key determinant of breast cancer outcome is the degree to which newly diagnosed cancers are treated correctly in a timely fashion. Available resources must be applied in a rational manner to optimize population-based outcomes. A multidisciplinary international panel of experts addressed the implementation of treatment guidelines and developed process checklists for breast surgery, radiation ...
We are accumulating evidence to suggest that 17(th) century Renaissance foodways -largely based on the old "Mediterranean dietary traditions"- may provide new nutraceutical management strategies against HER2-positive breast cancer disease in the 21st century. Epidemiological and experimental studies begin to support the notion that "The Sacred Law of Salads" (i.e., "raw vegetables... plenty of ...
Immunizations with the oncogenic protein Her-2/neu elicit Abs exerting diverse biological effects--depending on epitope specificity, tumor growth may be inhibited or enhanced. Trastuzumab (herceptin) is a growth-inhibitory humanized monoclonal anti-Her-2/neu Ab, currently used for passive immunotherapy in the treatment of breast cancer. However, Ab ...
The hormonal milieu at time of tumor surgery seems to have a significant impact on survival in premenopausal breast cancer patients. Indeed, surgery performed during the follicular phase of the menstrual cycle was suggested to correlate with a poor prognosis. To investigate the relationship between prognosis and menstrual cycle at time of surgery, we analyzed the expression of some markers ...
A systematic analytical approach combining tryptic and chymotryptic peptide mapping with a Mascot Error Tolerant Search (ETS) has been developed to detect and identify low level protein sequence variants, i.e., amino acid substitutions, in recombinant monoclonal antibodies. The reversed-phase HPLC separation with ultraviolet (UV) detection and mass spectral acquisition parameters of the peptide ...
Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number ...
Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammary glands from atypical hyperplasia to invasive carcinoma. It was previously observed that chronic administration of interleukin (IL)-12 increased tumor ...
Electron paramagnetic resonance (EPR) imaging using nitroxides as molecular probes is potentially a powerful tool for the detection and physiological characterization of micrometastatic lesions. Encapsulating nitroxides in anti-HER2 immunoliposomes at high concentrations, to take advantage of the "self-quenching" phenomenon of nitroxides, allows generation of robust EPR signals in ...
A highly efficient process using iron oxide magnetic nanoparticles (IO)-based immunomagnetic separation of tumor cells from fresh whole blood has been developed. The process involved polymer coated 30�nm IO that was modified with antibodies (Ab) against human epithelial growth factor receptor 2 (anti-HER2 or anti-HER2/neu) forming IO-Ab. HER2 is a cell ...
Epidermal growth factor receptor (EGFR) has become an attractive target for cancer molecular imaging and therapy. Affibody proteins against EGFR have been reported, and thus, we were interested in evaluating their potential for positron emission tomography (PET) imaging of EGFR positive cancer. An Affibody analogue (Ac-Cys-Z(EGFR:1907)) binding to EGFR was ...
The oligomerization and aggregation of the amyloid-beta (A beta) peptide, a cleavage product of the amyloid precursor protein predominantly 40 or 42 amino acids in length, has been implicated in the pathogenesis of Alzheimer's disease. The identification of A beta-binding agents, e.g., antibodies or peptides, constitutes a promising therapeutic approach. However, the amount of structural and ...
The epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer and is therefore an attractive target for treatment. (ZEGFR:1907)2 is a newly developed dimeric affibody molecule with high affinity to the extracellular part of EGFR. In this study, we evaluated the cytotoxic effects of (ZEGFR:1907)2 in combination with external radiation and the ...
Affinity reagents recognizing constant parts of antibody molecules are invaluable tools in immunotechnology applications, including purification, immobilization, and detection of immunoglobulins. In this article, murine IgG?, the primary isotype of monoclonal antibodies (mAbs) was used as target for selection of novel binders from a combinatorial ribosome display (RD) library of 10�� ...
Overexpression of epidermal growth factor receptor (EGFR) is associated with many types of cancers. It is of great interest to noninvasively image the EGFR expression in vivo. In this study, we labeled an EGFR-specific Affibody molecule (Eaff) with a near-infrared (NIR) dye IRDye800CW maleimide and tested the binding of this labeled molecule (Eaff800) in cell culture and ...
Overexpression of epidermal growth factor receptor (EGFR) in several types of malignant tumors correlates with disease progression. EGFR could, therefore, be an excellent candidate for targeted radionuclide diagnostics. However, the high natural expression of EGFR in the liver may be problematic. The aim of this study was to improve the tumor-to-liver ratio of radiolabeled epidermal growth factor ...
HER2 overexpression has been associated with a poor prognosis and resistance to therapy in breast cancer patients. However, quantitative estimates of this important characteristic have been limited to ex vivo ELISA essays of tissue biopsies and/or PET. We develop a novel approach in optical imaging, involving specific probes, not interfering with the binding of the therapeutic agents, thus, ...
Advanced ovarian cancer is largely incurable, but initially it is frequently confined to the i.p. space. We explored i.p. radioimmunotherapy in a mouse model of human ovarian cancer. Use of a targeted actinium-225 ((225)Ac) in vivo generator of alpha particles exploits the extreme, selective cytotoxicity of alpha particles, while providing a feasible half-life to enable delivery to tumor. (225)Ac ...
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 ...
Alpha-particles are suitable to treat cancer micrometastases because of their short range and very high linear energy transfer. Alpha-particle-emitter 213Bi based radioimmunotherapy has shown efficacy in a variety of metastatic animal cancer models, such as breast, ovarian, prostate cancer and leukemia. Its clinical implementation, however, is challenging due to the limited ...
PURPOSE To evaluate efficacy and safety of epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab as neoadjuvant treatment in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. PATIENTS AND METHODS Patients with centrally confirmed HER2-overexpressing breast cancer (? 2 cm or inflammatory) received four 3-week cycles epirubicin and ...
Purpose: Data have suggested that the molecular features of breast cancer are important determinants of outcome; however, few studies have correlated these features with locoregional recurrence (LRR). In the present study, we evaluated estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as predictors of LRR in patients with lymph node-negative ...
Multimodality molecular imaging should have potential for compensating the disadvantages and enhancing the advantages of each modality. Nuclear imaging is superior to optical imaging in whole body imaging and in quantification due to good tissue penetration of gamma rays. However, target specificity can be compromised by high background signal due to the always signal ON feature of nuclear probes. ...
This dissertation describes a novel Boron Neutron Capture Therapy (BNCT) application for the treatment of human epidermal growth factor receptor type 2 positive (HER2+) breast cancers. The original contribution of the dissertation is the development of the engineering simulation and the feasibility study of the radiation treatment protocol for this novel combination of BNCT and HER2+ breast cancer ...
BackgroundNanocarrier-based antibody targeting is a promising modality in therapeutic and diagnostic oncology. Single-walled carbon nanotubes (SWNTs) exhibit two unique optical properties that can be exploited for these applications, strong Raman signal for cancer cell detection and near-infrared (NIR) absorbance for selective photothermal ablation of tumors. In the present study, we constructed a ...
BACKGROUND: In this study, we asked whether anti-CD3-activated T cells (ATCs) from cord blood (CB) could be expanded and targeted to solid tumors or hematologic malignancies for infusions after unrelated CB stem cell transplant and whether cord blood ATCs (CBATCs) could reduce alloresponsiveness. STUDY DESIGN AND METHODS: CB mononuclear cells (MNCs) were activated with anti-CD3 (20?ng/mL) and ...
Targeted fluorophore-labeled contrast agents are moving toward translation to human surgical use. To prepare for future clinical use, we examined the performance of potential ligands targeting the epidermal growth factor receptor, ?5?3 integrins, and GLUT transporters for their suitability as directed contrast agents. Each agent was labeled with IRDye 800CW, and near-infrared dye with ...
The application of magnetic resonance imaging (MRI) to non-invasively assess disease biomarkers has been hampered by the lack of desired contrast agents with high relaxivity, targeting capability, and optimized pharmacokinetics. We have developed a novel MR imaging probe targeting to HER2, a biomarker for various cancer types and a drug target for anti-cancer therapies. This multimodal ...
Effective formulations of hydrophobic drugs for cancer therapies are challenging. To address this issue, we have sought to nanoscale artificial oil bodies (NOBs) as an alternative. NOBs are lipid-based particles which consist of a central oil space surrounded by a monolayer of oleosin (Ole)-embedded phospholipids (PLs). Ole was first fused with the anti-HER2/neu affibody ...
A great deal of effort has been made over the years to develop liposomes that have targeting vectors (oligosaccharides, peptides, proteins and vitamins) attached to the bilayer surface. Most studies have focused on antibody conjugates since procedures for producing highly specific monoclonal antibodies are well established. Antibody conjugated liposomes have recently attracted a great deal of ...
BackgroundOligomeric and fibrillar aggregates of the amyloid ?-peptide (A?) have been implicated in the pathogenesis of Alzheimer's disease (AD). The characterization of A? assemblies is essential for the elucidation of the mechanisms of A? neurotoxicity, but requires large quantities of pure peptide. Here we describe a novel approach to the recombinant production of A?. The method is based on the ...
BackgroundThe effects of the olive oil-rich Mediterranean diet on breast cancer risk might be underestimated when HER2 (ERBB2) oncogene-positive and HER2-negative breast carcinomas are considered together. We here investigated the anti-HER2 effects of phenolic fractions directly extracted from Extra Virgin Olive Oil (EVOO) in cultured human breast cancer cell lines.MethodsSolid phase extraction ...
PurposeTo evaluate the risk of recurrence in women diagnosed with T1a and T1b, node-negative, human epidermal growth factor receptor 2 (HER2) �positive breast cancer.MethodsWe reviewed 965 T1a,bN0M0 breast cancers diagnosed at our institution between 1990 and 2002. Dedicated breast pathologists confirmed HER2 positivity if 3+ by immunohistochemistry or if it had a ratio of 2.0 or greater by ...
Successful RAIT strategies depend upon selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle. Small, engineered anti-tumor antibody fragments are capable of rapid, highly specific tumor targeting in immunodeficient mouse models. We hypothesized that their rapid systemic elimination would make them ideal radioisotope carriers for the ...
Human epidermal growth factor receptor 2 (HER2) testing is an essential part of pathological assessment in breast cancer patients, as HER2 provides not only prognostic but also predictive information on response to targeted therapy. So far, HER2 test accuracy of immunohistochemistry/in situ-hybridization techniques is still under debate, and more reliable and robust technologies are needed. To ...
Approximately one third of patients with advanced human epidermal growth factor receptor 2 (HER-2)/neu-positive breast cancer respond to trastuzumab monotherapy, a humanized anti-HER-2/neu antibody. However, de novo and acquired antibody resistance is one of the major limitations of trastuzumab therapy warranting the search for other therapeutic ...
We previously reported the formulation and physical properties of HER2 (human epidermal growth factor receptor 2)-specific affibody (ZHER2:342-Cys) conjugated thermosensitive liposomes (HER2(+)affisomes). Here we examined localized delivery potential of these affisomes by monitoring cellular interactions, intracellular uptake, and hyperthermia-induced effects on drug delivery. ...
Raman spectroscopy is an optical imaging method that is based on the Raman effect, the inelastic scattering of a photon when energy is absorbed from light by a surface. Although Raman spectroscopy is widely used for chemical and molecular analysis, its clinical application has been hindered by the inherently weak nature of the Raman effect. Raman-silica-gold-nanoparticles (R-Si-Au-NPs) overcome ...
The human epidermal growth factor receptor 2 (HER2) is specifically overexpressed in tumors of several cancers, including an aggressive form of breast cancer. It is therefore a target for both cancer diagnostics and therapy. The 58 amino acid residue Zher2 affibody molecule was previously engineered as a high-affinity binder of HER2. Here we determined the structure of Zher2 ...
Block copolymer-based vesicles have recently garnered a great deal of interest as nanoplatforms for drug delivery and molecular imaging applications due to their unique structural properties. These nanovesicles have been shown to direct their cargo to disease sites either through enhanced permeability and retention or even more efficiently via active targeting. Here we show that the efficacy of ...
PURPOSE: Cancers overexpressing the HER2/neu gene are usually more aggressive and are associated with poor prognosis. Although trastuzumab has significantly improved the outcome, many tumors do not respond or acquire resistance to current therapies. To provide an alternative HER2-targeted therapy, we have developed and characterized a novel recombinant protein combining an HER2-specific ...
Purpose: The aim of the present study was to investigate if treatment with lysosomotropic weak bases could increase the intracellular retention of radiohalogens and thereby increase the therapeutic effect of radionuclide tumor targeting. Methods and Materials: Four different lysosomotropic bases, chloroquine, ammonium chloride, amantadine, and thioridazine, were investigated for their ability to ...
Two conjugated polymers, poly[9,9-bis(2-(2-(2-methoxyethoxy)ethoxy)ethyl) fluorenyldivinylene] (PFV) and the PFV derivative containing 10 mol % 2,1,3-benzothiadiazole (BT) units (PFVBT), have been synthesized and employed to fabricate conjugated polymer loaded nanospheres for simultaneous discrimination of mixed live cancer cells in one solution. The incorporation of BT units into the PFV backbone ...
We analyzed the thermodynamic basis for improvement of a binding protein by disulfide engineering. The Z(SPA)(-)(1) affibody binds to its Z domain binding partner with a dissociation constant K(d) = 1.6 microM, and previous analyses suggested that the moderate affinity is due to the conformational heterogeneity of free Z(SPA)(-)(1) rather than to a suboptimal binding ...
The efficacy of adenovirus (Ad)-based gene therapy of solid tumors, such as prostate cancer, is limited. One of the many problems is that the virus infects many different cell types in the body, resulting in high toxicity, while the target cancer cells are often less prone to wild type Ad infection. Our aim was to develop genetically de- and re-targeted Ad vectors to reduce off-target effects and ...
PURPOSE: Two-helix scaffold proteins (~ 5�kDa) against human epidermal growth factor receptor type 2 (HER2) have been discovered in our previous work. In this research we aimed to develop an (18)F-labeled two-helix scaffold protein for positron emission tomography (PET) imaging of HER2-positive tumors. METHODS: An aminooxy-functionalized two-helix peptide (AO-MUT-DS) with high HER2 binding ...
