Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MDX-H210 is a chemically, cross-linked, half-humanized bispecific antibody composed of F(ab') fragment from monoclonal antibody (mAb) H22 that binds to the high-affinity receptor Fc gamma RI and F(ab') of mAb 520C9 that recognizes the erbB-2 (HER2/neu) oncoprotein. In a previous trial, the murine bispecific, MDX-210 at a dose of 7 mg/m2, was well tolerated and activated monocytes and macrophages in vivo in doses as low as 0.35 mg/m2. In our multidose trial, granulocyte-macrophage colony-stimulating factor, which increases and activates potential effector cells, was given on days 1-4 at 250 micrograms/m2 s.c. and MDX-H210 was given on day 4 weekly for 4 consecutive weeks. Thirteen patients were treated at dose levels of 1, 3.5, 7, 10, 15, and 20 mg/m2 without dose-limiting toxicity. Fever, chills, and rigors occurred during and up to 2 h postinfusion and correlated with the time to peak levels of tumor necrosis factor-alpha (median 88.2 pg/ml; range 15.6-887 pg/ml) and interleukin-6 (median 371 pg/ml; range 175-2,149 pg/ml). By the fourth consecutive week of treatment the side effects and cytokine levels decreased significantly. Human antibispecific antibody (HABA) levels were increased by 200- to 500-fold above pretreatment levels in 5 of 11 evaluable patients after 3 weeks of treatment. The monocyte and granulocyte population increased on days 4 and 11 (median 44%; range 18-68% and 42%; 19-71%), respectively, for monocytes and (60%; 43-75% and 74%; 54-82%) on days 4 and 11 for granulocytes. There was a significant decrease in the monocyte populations immediately after MDX-H210 administration (median decrease 73%; range 42-94%) and (52%; 12-72%) on days 4 and 11, respectively. Ten patients completed 4 weeks of treatment. One patient had a 48% reduction in an index lesions and six patients had stable disease at the time of evaluation. Three patients progressed before the fourth week. The therapy was generally well tolerated with toxicity, primarily, limited to the days of treatment.
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PMID:A pilot trial of GM-CSF and MDX-H210 in patients with erbB-2-positive advanced malignancies. 1040 39

T helper type1 (Th1) or type2 (Th2) cells were induced from naive Th cells obtained from ovalbumin-specific T cell receptor (TCR) transgenic mice. Th1 cells producing interferon gamma (IFNgamma) exhibited stronger antigen-specific cytotoxicity against ovalbumin-(323-339)-peptide-pulsed A20 tumor cells than did Th2 cells. To develop a general method for applying antigen-nonspecific Th1 cells to tumor immunotherapy, we examined the targeting of Th1 cells to tumor cells using a bispecific antibody (bsAb) consisting of anti-(mouse CD3) mAb and anti-(human c-ErbB-2) mAb. When ovalbumin-specific Th1 or Th2 cells were cocultured with c-erbB-2-positive transfectants (CMS7HE), neither type of cell showed significant cytotoxicity or cytokine production in response to tumor cells. However, addition of bsAb resulted in the triggering of both Th1 and Th2 cells. Th1 cells showed higher levels of bsAb-dependent cytotoxicity against CMS7HE tumor cells than did Th2 cells. The targeting of Th1 cells to CMS7HE tumor cells by bsAb also triggered the production of cytokines such as IFNgamma, interleukin-2 and tumor necrosis factor alpha (TNFalpha). The released TNFalpha was demonstrated to be a critical cytolytic factor in bsAb-mediated cytotoxicity by Th1 cells. Finally, Th1 cells were demonstrated to show antitumor activity in vivo against human c-erbB-2-positive tumor cells implanted in nude mice. These results suggest that Th1 cells are useful effector cells for the application to adoptive tumor immunotherapy in conjunction with bsAb.
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PMID:Tumor-specific targeting of T helper type 1 (Th1) cells by anti-CD3 x anti-c-ErbB-2 bispecific antibody. 1055 May 50

Interleukin (IL)-6, a multifunctional regulator of immune response, hematopoiesis, and acute phase reactions, has also been shown to regulate cancer cell proliferation. We have investigated IL-6 signaling pathways and cellular responses in the T47D breast carcinoma cell line. The IL-6-type cytokines, IL-6 and oncostatin M, simultaneously inhibited cell proliferation and increased cell migration. In T47D cells, IL-6 stimulated the activation of Janus-activated kinase 1 tyrosine kinase and signal transducers and activators of transcription (STAT) 1 and STAT3 transcription factors. Expression of dominant negative STAT3 in the cells strongly reduced IL-6-mediated growth inhibition but did not prevent IL-6-induced cell migration. IL-6 treatment led to activation of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase (PI3K) pathways. Inhibition of MAPK or PI3K activity reversed IL-6- and oncostatin M-stimulated migration. Because cross-talk between cytokine receptors and members of the ErbB family of receptor tyrosine kinases has been described previously, we have examined their interaction in T47D cells. Down-regulation of ErbB receptor activity, through the use of specific pharmacological inhibitors or dominant negative receptor constructs, revealed that IL-6-induced MAPK activation was largely dependent on epidermal growth factor (EGF) receptor activity, but not on ErbB-2 activity. Using a monoclonal antibody that interferes with EGF receptor-ligand interaction, we have shown that in T47D cells, IL-6 cooperates with an EGF receptor autocrine activity loop for signaling through the MAPK and PI3K pathways and for cell migration. Both the tyrosine phosphatase SHP-2 and the multisubstrate docking molecule Gab1, which are potential links between IL-6 and the MAPK/PI3K pathways, were constitutively associated with the active EGF receptor. On IL-6 stimulation, SHP-2 and Gab1 were recruited to the gp130 subunit of the IL-6 receptor and tyrosine phosphorylated, allowing downstream signaling to the MAPK and PI3K pathways. Thus, in T47D breast carcinoma cells, IL-6 acts in synergy with EGF receptor autocrine activity to signal through the MAPK/PI3K pathways. Cooperation between IL-6 and the EGF receptor in T47D breast carcinoma cells illustrates how a combination of multiple stimuli, either exogenous or endogenous, may result in synergistic cellular responses.
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PMID:Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. 1119 91

The goal of this study was to evaluate, in patients with prostate cancer, the toxicity profile and biologic activity of the bispecific antibody MDXH210, which has specificity for the non-ligand-binding site of the high-affinity immunoglobulin G receptor (Fc gamma RI) and the extracellular domain of the HER-2/neu proto-oncogene product. Patients with prostate cancer that expressed HER-2/neu were entered into a phase I dose-escalation trial of MDXH210. Patients received an intravenous infusion MDXH210 during a period of 2 h three times per week for 2 weeks and were monitored for toxicity. Pharmacokinetic and pharmacodynamic parameters were measured and included the biologic end points of monocyte-bound MDXH210, cytokine production, and clinical response. Seven patients were treated with MDXH210 doses ranging from 1 to 8 mg/m2. In general, MDXH210 was well tolerated, with only mild infusion-related malaise, fever, chills, and myalgias. No dose-limiting toxic effects were observed. Biologic effects included induction of low plasma concentrations of tumor necrosis factor-alpha and interleukin-6 observed immediately after MDXH210 infusion and 70% saturation of circulating monocyte-associated Fc gamma RI with MDXH210 at a dose level of 4 to 8 mg/m2. Five of six patients had stable prostate-specific antigen levels during the course of 40 days or more. Circulating plasma HER-2/neu levels decreased by 80% at days 12 and 29 (p = 0.03 and 0.06, respectively, by the Wilcoxon signed rank test). MDXH210 can be given safely to patients with HER-2/neu-positive prostate cancer in doses of at least 8 mg/m2. At the doses studied, biologic activity was demonstrated and characterized by binding of MDXH210 to circulating monocytes, release of monocyte-derived cytokines, a decrease in circulating HER-2/neu, and short-term stabilization of prostate-specific antigen levels.
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PMID:Phase I pilot trial of the bispecific antibody MDXH210 (anti-Fc gamma RI X anti-HER-2/neu) in patients whose prostate cancer overexpresses HER-2/neu. 1121 Nov 51

Studies from our laboratory and others have established that both mononuclear phagocytes and neutrophils mediate very efficient cytotoxicity when targeted through Fc receptors using a suitable monoclonal or bispecific antibody (BsAb). Cross-linking an Fc receptor for IgG (FcgammaR) triggers multiple anti-tumor activities including superoxide generation, cytokine and enzyme release, phagocytosis and antibody-dependent cellular cytotoxicity (ADCC). In this report, using unfractionated leukocytes and two color flow cytometric analysis, we describe the phagocytic capacity of peripheral blood polymorphonuclear cells (PMN) and monocytes isolated from patients enrolled in a phase I clinical trial of MDX-H210 given in combination with IFNgamma. MDX-H210 is a BsAb targeting the myeloid trigger molecule FcgammaRI and the HER-2/neu proto-oncogene product overexpressed on a variety of adenocarcinomas. In this trial, cohorts of patients received escalating doses of MDX-H210 3 times per week for 3 weeks. Interferon-gamma (IFNgamma) was given 24 h prior to each BsAb infusion. Our results demonstrate that monocytes from these patients were inherently capable of phagocytosing the HER-2/neu positive SK-BR-3 cell line and that addition of MDX-H210 into the assay significantly enhanced the number of targets phagocytosed. Two days after administration of an immunologically active dose of MDX-H210 (10 mg/m2), monocytes from these patients were able to phagocytose greater amounts of target cell material, indicating that these cells remained armed with functionally sufficient BsAb for at least 48 h. PMN from these patients very efficiently mediated phagocytosis through FcgammaRI after being treated with IFNgamma, but not before. We conclude that phagocytosis is not only an efficient mechanism of myeloid cell-mediated cytotoxicity, but may also be a mechanism by which antigens from phagocytosed cells can enter a professional antigen presenting cell for processing and presentation.
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PMID:Bispecific antibody-targeted phagocytosis of HER-2/neu expressing tumor cells by myeloid cells activated in vivo. 1122 77

Recently there has been a renewed interest in developing vaccines for use in cancer treatment. Part of this interest stems from a better understanding of the immune system, the identification of a number of T-cell-specific tumor antigens, more effective adjuvants, and the ability to construct more immunogenic molecules using recombinant DNA techniques. Studies from several laboratories have shown that breast cancer patients have preexisting immunity to the HER-2/neu oncoprotein receptor (HER-2) in the form of elevated antibody titers and T-cell immunity. Preclinical studies showed enhanced delayed-type hypersensitivity and cytotoxic T-lymphocyte precursors in spleens from animals immunized with several human leukocyte antigen class I and class II peptides derived from the HER-2 protein. Phase I trials of these peptides combined with the cytokine granulocyte-macrophage colony-stimulating factor as a part of therapy in patients with HER-2-positive cancers have shown minimal local toxicity, along with enhanced helper T-cell activity and antibody production in patients with minimal disease. Increases in cytotoxic T-lymphocyte precursor activity were less frequent, but in some cases could be enhanced when patient lymphocytes were incubated ex vivo with the proinflammatory cytokine interleukin-12. Other preclinical studies designed to enhance HER-2 peptide immunogenicity are in progress. Additional current and future clinical trials using HER-2-derived vaccines will be discussed.
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PMID:Clinical trials of HER-2/neu-specific vaccines. 1123 31

HER2/neu-derived peptides inducing MHC class II-restricted CD4+ T helper lymphocyte (Th) responses, although critical for tumour rejection, are not thoroughly characterized. Here, we report the generation and characterization of CD4+ T cell clones specifically recognizing a HER-2/neu-derived peptide (776-788) [designated HER2(776-788)]. Such clones yielded specific proliferative and cytokine [gamma-interferon(IFN)-gamma] responses when challenged with autologous dendritic cells (DCs) loaded with HER2(776-788). By performing blocking studies with monoclonal antibodies (MAbs) and by using DCs from allogeneic donors sharing certain HLA-DR alleles, we found that HER2(776-788) is a promiscuous peptide presented, at least, by DRB5*0101, DRB1*0701 and DRB1*0405 alleles. One TCRV beta 6.7+ clone recognized the HLA-DRB5*0101+ FM3 melanoma cell line transfected with a full length HER-2/neu cDNA. Moreover, this clone recognized the HER-2/neu+ SKBR3 breast cancer cell line induced to express HLA-DR, thus demonstrating that HER2(776-788) represents a naturally processed and presented epitope. Our data demonstrate that helper peptide HER2(776-788) represents a promiscuous epitope binding to at least three HLA-DR alleles, thus offering a broad population coverage. The use of antigenic peptides presented by major histocompatibility complex (MHC) class II in addition to those presented by class I may improve the therapeutic efficacy of active immunization.
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PMID:Peptide HER2(776-788) represents a naturally processed broad MHC class II-restricted T cell epitope. 1172 Apr 40

HER-2/neu peptides have recently been shown to induce a proliferative response by peripheral CD4(+) T cells in breast cancer patients. To investigate potential differences in the local cellular immune response between breast cancer patients with and without nodal metastases, lymphocytes were isolated from axillary lymph nodes from patients with breast cancer, and proliferative and cytokine responses to HER-2/neu peptides were determined. Freshly isolated lymphocytes from lymph nodes of 7 women undergoing surgery for invasive breast cancer were plated at 20 x 10(5) cells per well in triplicate. Cells were stimulated with HER-2/neu peptides at 50 microg/ml and with control antigens. Incorporation of tritium-labeled thymidine was determined 4 days later. The levels of the cytokines interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and IL-10 were determined at priming and at restimulation with HER-2/neu peptides using a cytokine-specific, double-sandwich, enzyme-linked immunosorbent assay (ELISA). Lymphocytes isolated from the axillary lymph nodes of the patients mounted significant cellular immune response to HER-2/neu peptides, manifested by proliferation and specific cytokine elaboration. Proliferative responses to HER-2/neu peptides were seen in lymphocytes of patients with and without overexpression of HER-2/neu in the primary tumor. In some patients, the proliferative response to HER-2/neu peptides in lymphocytes from lymph nodes with metastases was absent or blunted compared with the response in lymphocytes from lymph nodes without metastases from the same patient (p < 0.05). HER-2/neu peptides induced a predominantly T helper type 1 (Th1) pattern of cytokine response in nodal lymphocytes isolated from breast cancer patients. A Th1-specific cytokine production pattern was maintained at priming and restimulation with HER-2/neu peptides and was amplified with IL-12 costimulation. These results indicate that HER-2/neu peptides can activate T cells in draining lymph nodes from women with invasive breast cancer. This activation is associated with a predominantly Th1 cytokine response, which suggests that conditioning with HER-2/neu peptides may be of value in the development of breast cancer vaccines.
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PMID:Axillary lymph node cellular immune response to HER-2/neu peptides in patients with carcinoma of the breast. 1206 Apr 97

A novel approach to cancer gene therapy is to implant microcapsules containing nonautologous cells engineered to secrete molecules with antineoplastic properties. The efficacy of this treatment is now tested in a mouse model bearing HER-2/neu-positive tumors. Nonautologous mouse myoblasts (C(2)C(12)) were genetically modified to secrete interleukin-2 linked to the Fv region of a humanized antibody with affinity to HER-2/neu. The resulting fusion protein, sFvIL-2, would encompass immune-stimulatory cytokine activity now targeted to the HER-2/neu-expressing tumor. These recombinant cells were then immunoprotected with alginate-poly-L-lysine-alginate microcapsules before implantation into tumor-bearing mice. Treatment with these encapsulated cells led to a delay in tumor progression and prolonged survival of the animals. The long-term efficacy was limited by an inflammatory reaction against the implanted microcapsules probably because of the secreted cytokine and antigenic response against the xenogeneic fusion protein itself. However, over the short term (initial 2 weeks), efficacy was confirmed when a significant amount of biologically active interleukin-2 was detected systemically, and targeting of the fusion protein to the HER-2/neu-expressing tumor was shown immunohistochemically. The tumor suppression in the treated animals was associated with increased apoptosis and necrosis in the tumor tissue, thus demonstrating successful targeting of the antiproliferative effect to the tumors by this delivery paradigm. In conclusion, this new approach to systemic cancer gene therapy needs to be modified to provide long-term delivery, but has demonstrated short-term efficacy and potential to become a cost-effective, benign, and non-viral-based adjunct to the current armory of anticancer strategies.
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PMID:A novel approach to tumor suppression with microencapsulated recombinant cells. 1213 69

Chimeric receptors comprising of the T-cell receptor-zeta cytoplasmic signalling chain fused to an extracellular ligand-binding domain of a single-chain antibody (scFv) have served as effective tools for redirecting cytotoxic T lymphocytes (CTL) against tumour cells. In this report, we constructed a chimeric scFv/zeta gene composed of the variable regions of an HER-2/neu-specific monoclonal antibody (MAb) joined to the TCR-zeta chain. The scFv(anti-HER-2/neu)/zeta chimeric gene was successfully expressed as a functional surface receptor in the MD.45 CTL hybridoma (MD.45-HER/zeta). More importantly, the scFv(anti-HER-2/neu)/zeta receptor was functionally active, since it triggered cytokine secretion by the MD.45-HER/zeta cells upon recognition of HER-2/neu-positive (+) tumour cell lines, or primary tumour cells from patients with HER-2/neu(+) cancers. The MD.45-HER/zeta-transduced cells also lysed HER-2/neu(+) target cells in vitro with high specificity. We tested the antitumour efficacy of scFv(anti-HER-2/neu)/zeta expressing MD.45 cells in severe combined immunodeficiency disease mice/human and murine tumour models. The adoptively transferred MD.45-HER/zeta cells both slowed significantly the growth of human FM3 melanoma or murine ALC leukaemic cells both transfected to express HER-2/neu. Our data demonstrate the feasibility of redirecting MD.45 CTL with the scFv(anti-HER-2/neu)/zeta chimeric receptor to respond specifically against HER-2/neu expressing tumour cells in vitro and in vivo. Moreover, they make it likely that T cells transduced with the same chimeric gene might be utilised in the treatment of patients with HER-2/neu(+) tumours.
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PMID:Redirecting mouse T hybridoma against human breast and ovarian carcinomas: in vivo activity against HER-2/neu expressing cancer cells. 1269 99


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