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)

Bispecific murine monoclonal antibody 2B1, possessing dual specificity for the human c-erbB-2 protooncogene product and human Fc gamma receptor III (CD16) was evaluated for the ability to promote specific lysis of c-erbB-2-positive tumor cells in vitro. In short-term 51Cr release assays with human mononuclear cells as effectors and SK-Br-3 human breast cancer cells as targets, neither parental antibody of 2B1 mediated significant specific lysis, but bispecific antibody was as active as a chemical heteroconjugate, with 5 ng/ml of 2B1 causing half-maximal lysis at an effector/target ratio of 20:1 and 2 ng/ml 2B1 causing half-maximal lysis at an E/T ratio of 40:1. The cytotoxic targeting activity of 2B1 F(ab')2 fragment was the same as that of whole bispecific antibody, and the activity of whole 2B1 was not reduced when assays were performed in 100% autologous human serum, indicating that 2B1 binds effector cells through the CD16-binding site derived from parental antibody 3G8 rather than through its Fc portion. Variable inhibition of 2B1-mediated lysis was observed when autologous polymorphonuclear leukocytes from different donors were added to mononuclear effector cells at a 2:1 ratio; this inhibition was overcome at higher antibody concentration. 2B1 bispecific monoclonal antibody was also able to mediate targeted cytolysis using whole human blood as a source of effector cells or using effector or target cells derived from ovarian cancer patients.
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PMID:In vitro cytotoxic targeting by human mononuclear cells and bispecific antibody 2B1, recognizing c-erbB-2 protooncogene product and Fc gamma receptor III. 136 Aug 72

New strategies are required to clinically exploit the ability of monoclonal antibodies to target tumor for lysis by cellular effector mechanisms. In this report we examine the therapeutic effects of 2B1, a bispecific monoclonal antibody with specificity for the extracellular domain of the c-erbB-2 oncogene product and the human Fc gamma receptor, Fc gamma RIII (CD16), describe the characteristics and limitations of this model, and examine the mechanisms underlying the observed responses. The model uses SK-OV-3 human ovarian carcinoma xenografts in scid mice. These cells are susceptible to 2B1-directed lysis by human peripheral blood lymphocytes or lymphokine-activated killer cells, and maintain c-erbB-2 expression in vivo. 125I-labeled 2B1 selectively accumulates in tumor, with a peak of 10.5% injected dose/g of tumor 24 h following its i.v. injection. However, the selectivity of this binding is lessened by 2B1 accumulation in the lungs and other normal organs and persistence in the blood. This is caused by antibody binding to murine lung, colon, stomach, and skin expressing the epitope recognized by the anti-c-erbB-2 component of 2B1 in tumor-bearing, but not normal mice. In treatment studies using various permutations of antibody, human peripheral blood lymphocytes or lymphokine-activated killer cells and interleukin 2, cellular therapy alone had minimal effects on SK-OV-3 xenograft growth, but significantly improved when 2B1 treatment was incorporated. Median survivals increased from 80 +/- 3.5 days with no therapy to 131 +/- 7.3 days following therapy with 100 micrograms 2B1, interleukin 2, and human peripheral blood lymphocytes, with 70% of animals exhibiting no evidence of tumor at day 150. These effects were preserved when the cells were administered in human serum. In contrast, human serum abolished the antitumor effects of 520C9, which is the parent anti-c-erbB-2 antibody of 2B1. Thus 2B1-based therapy has therapeutic effects, without obvious toxicity, despite the targeting of this antibody to normal murine tissues. Since combinations of 2B1 and interleukin 2 may have antitumor properties, mechanisms other than bispecific monoclonal antibody-promoted conjugation of c-erbB-2 antigen-expressing tumor to CD16-expressing effector cells may be involved.
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PMID:A human tumor xenograft model of therapy with a bispecific monoclonal antibody targeting c-erbB-2 and CD16. 809 31

Bispecific monoclonal antibodies (BsmAb) can be used to specifically target tumor cells for cytotoxicity mediated by defined effector cells. One such BsmAb, 2B1, targets the extracellular domains of both the c-erbB-2 protein product of the HER-2/neu oncogene and Fc gamma RIII (CD16), the Fc gamma receptor expressed by human natural killer cells, neutrophils, and differentiated mononuclear phagocytes. 2B1 promotes the conjugation of cells expressing these target antigens. It efficiently promotes the specific lysis of tumor cells expressing c-erbB-2 by human NK cells and macrophages over a broad concentration range. 2B1 selectively targets c-erbB-2-positive human tumor xenografts growing in immunodeficient SCID mice. Treatment of such mice with 2B1 plus interleukin 2 (IL-2) inhibits the growth of early, established human tumor xenografts overexpressing c-erbB-2. A phase I clinical trial of 2B1 has been initiated to determine the toxicity profile and maximum tolerated dose (MTD) of this BsmAb and to examine the biodistribution of the antibody and the biologic effects of treatment. Preliminary results of this trial indicate that the dose-limiting toxicity for patients with extensive prior bone marrow-toxic therapy is thrombocytopenia for as yet undetermined reasons. Toxicities of fevers, rigors, and associated constitutional symptoms are explained, in part, by treatment-induced systemic expression of cytokines, such as tumor necrosis factor-alpha. Circulating, functional BsmAb is easily detectible in treatment patients' sera and exhibits complex elimination patterns. HAMA and anti-idiotypic treatment-induced antibodies are induced by 2B1 treatment. Some preliminary indications of clinical activity have been observed. BsmAb therapy targeting tumor antigens and Fc gamma RIII has potent immunologic effects. Future studies will include the development of more relevant animal models for BsmAb therapy targeting human Fc gamma RIII. The ongoing phase I trial will be completed to identify the MTD for patients without extensive prior bone marrow-toxic chemotherapy and radiation. A phase II clinical trial of 2B1 therapy in women with metastatic breast cancer is planned, as is a phase I trial incorporating treatment with both 2B1 and IL-2.
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PMID:Clinical development of 2B1, a bispecific murine monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. 858 84

Immunotherapies directed to the proto-oncogene product HER-2/neu, which is overexpressed on a subset of breast and other carcinomas, currently receive considerable attention. We have investigated cell-mediated effector mechanisms of HER-2/neu antibodies against breast cancer cell lines. Compared to unfractionated control blood, whole blood from patients during granulocyte colony-stimulating factor (G-CSF) treatment exhibits significantly enhanced lysis (P < 0.001) of SK-BR-3 cells in the presence of HER-2/neu antibody 520C9. The extent of tumor cell killing correlated positively (r = 0.74) to polymorphonuclear neutrophil (PMN) blood counts. Fractionation of whole blood into plasma, mononuclear cells, and PMNs showed major killing capacity to reside in the granulocyte fraction. PMNs were efficiently cytolytic with a panel of HER-2/neu antibodies and against various breast cancer cell lines. Experiments with blocking antibodies to Fc(gamma)R documented Fc(gamma)RII (CD32) as the major trigger molecule for monoclonal antibody 502C9-mediated cytotoxicity. Killing via 520C9 was significantly influenced by an allotypic polymorphism of Fc(gamma)RIIa, the CD32 molecule expressed on PMNs. In reverse antibody-dependent cell-mediated cytotoxicity experiments with a panel of HER-2/neu-directed bispecific antibodies, Fc(gamma)RIII (CD16) proved to be an efficient trigger molecule in blood from healthy volunteers. During G-CSF treatment, however, Fc(gamma)RI (CD64)-expressed on monocytes and G-CSF primed, but not on healthy donor PMNs-became the predominant cytotoxic trigger molecule. Thus, G-CSF application increased effector cell numbers for HER-2/neu-directed immunotherapy, and G-CSF primed PMNs proved particularly effective with a [HER-2/neu x Fc(gamma)RI] bispecific antibody. These findings support clinical trials with HER-2/neu-directed antibodies in combination with G-CSF in breast cancer patients overexpressing HER-2/neu.
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PMID:Preclinical studies with Fc(gamma)R bispecific antibodies and granulocyte colony-stimulating factor-primed neutrophils as effector cells against HER-2/neu overexpressing breast cancer. 904 47

The bispecific monoclonal antibody (bsmAb) 2B1, targeting the extracellular domain of c-erbB-2, the protein product of the HER-2/neu proto-ocogene, and Fc gamma RIII (CD16), expressed by human natural killer cells, neutrophils and differentiated monocytes, mediates the specific cytotoxic activity of these effector cells to tumor cells. A group of 24 patients with c-erbB-2-overexpressing tumors were treated with intravenously administered 2B1 in a phase I clinical trial and followed after treatment to evaluate the diversity and extent of the 2B1-induced humoral immune responses. As expected, 17 of 24 patients developed human anti-(murine Ig) antibodies (HAMA) to whole 2B1 IgG in a range from 100 ng/ml to more than 50000 ng/ml; 10 of these patients (42%) had strong (at least 1000 ng/ml) HAMA responses, some of which were still detectable at day 191. These responses were usually associated with similar reactivity to the F(ab')2 fragments of the parental antibodies 520C9 (anti-c-erbB-2) and 3G8 (anti-CD16). We sought evidence of an idiotypic cascade induction, indicating a prolonged specific treatment-induced effect on at least one selected target of 2B1. Using competition-based enzyme-linked immunosorbent assays, specific anti-idiotypic antibodies (Ab2) were detectable against 520C9 in 11 patients and against 3G8 in 13 patients. Peak anti-idiotypic antibodies generally occurred 3-5 weeks from treatment initiation, with a downward trend thereafter. There was a statistically significant correlation among the induction of significant HAMA responses, anti-idiotypic antibody production and the development of antibodies to c-erbB-2. The anti-c-erbB-2 responses, which were distinct from anti-anti-idiotypic (Ab3) antibodies, were detected in the post-treatment sera of 6/16 patients examined. No obvious correlation could be made between the development of humoral immune responses, the dose received, and the clinical response. Future investigation involving 2B1 therapy will concentrate on investigating an association of these humoral responses to any c-erbB-2-specific cellular responses. Manipulations of 2B1 therapy effects that augment immunity to c-erbB-2 could provide additional avenues for immunotherapy with this and other bispecific antibodies.
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PMID:Induction of multiple anti-c-erbB-2 specificities accompanies a classical idiotypic cascade following 2B1 bispecific monoclonal antibody treatment. 924 61

Studies with gene-modified mice have recently reinforced the importance of Fc receptor-mediated effector mechanisms for the therapeutic efficacy of rituxan and herceptin - two clinically approved antibodies for the treatment of tumor patients. We investigated Fc receptor-dependent tumor cell killing by mononuclear and granulocytic effector cells - comparing human IgG1 antibodies against CD20 or HER-2/neu with their respective FcgammaRI (CD64)-, FcgammaRIII (CD16)-, or FcalphaRI (CD89)-directed bispecific derivatives. With blood from healthy donors as effector source, human IgG1 and FcgammaRIII (CD16)-directed bispecific antibodies proved most effective in recruiting mononuclear effector cells, whereas tumor cell killing by granulocytes was most potently triggered by FcalphaRI-directed bispecific constructs. Granulocyte-mediated tumor cell lysis was significantly enhanced when blood from G-CSF- or GM-CSF-treated patients was investigated. Interestingly, however, both myeloid growth factors improved effector cell recruitment by different mechanisms, which were furthermore dependent on the tumor target antigen, and on the selected cytotoxic Fc receptor.
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PMID:Mechanisms of G-CSF- or GM-CSF-stimulated tumor cell killing by Fc receptor-directed bispecific antibodies. 1122 72

The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20% of breast adenocarcinomas and is recognized by a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody-dependent cell cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (FcgammaRIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin-2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2. We tested IL-2-activated NK cells against Her2/neu+ (MCF-7Her2/neu) and Her2/neu- (MDA-468) breast cancer cell lines in a 4-h 51Cr-release cytotoxicity assay in the presence or absence of rhu4D5 mAb (effector : target ratio = 10 : 1). Specific lysis of rhu4D5-coated MCF-7Her2/neu and MDA-468 target cells by IL-2-activated NK cells was 35% and 3%, respectively (p < 0.05). Lysis was less than 5% when targets were treated with either the non-humanized mu4D5 mAb or control huIgG. Lysis of rhu4D5-coated MCF-7Her2/neu cells was inhibited by 80 % when NK cells were pre-treated with an anti-Fc receptor antibody prior to use in the cytotoxicity assay. Enhanced ADCC of MCF-7Her2/neu target cells was seen when the effector cells consisted of mononuclear cells obtained from a patient demonstrating significant expansion of NK cells secondary to therapy with low-dose IL-2. Serum from patients receiving infusions of rhu4D5 mAb could substitute for exogenous antibody in the ADCC assay. NK cells activated by rhu4D5-coated tumor cells in the presence of IL-2 also produced large amounts of IFN-gamma with concomitant up-regulation of cell-surface activation markers CD25 and CD69. These results lend support to the concurrent use of rhu4D5 mAb and IL-2 therapy in patients with cancers that express the Her2/neu oncogene.
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PMID:Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells. 1159 78