Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2B1 is a bispecific murine monoclonal antibody (BsMAb) with specificity for the c-erbB-2 and Fc gamma RIII extracellular domains. This BsMAb promotes the targeted lysis of malignant cells overexpressing the c-erbB-2 gene product of the HER2/neu proto-oncogene by human natural killer cells and mononuclear phagocytes expressing the Fc gamma RIII A isoform. In a Phase I clinical trial of 2B1, 15 patients with c-erbB-2-overexpressing tumors were treated with 1 h i.v. infusions of 2B1 on days 1, 4, 5, 6, 7, and 8 of a single course of treatment. Three patients were treated with daily doses of 1.0 mg/m2, while six patients each were treated with 2.5 mg/m2 and 5.0 mg/m2, respectively. The principal non-dose-limiting transient toxicities were fevers, rigors, nausea, vomiting, and leukopenia. Thrombocytopenia was dose limiting at the 5.0 mg/m2 dose level in two patients who had received extensive prior myelosuppressive chemotherapy. Murine antibody was detectable in serum following 2B1 administration, and its bispecific binding properties were retained. The pharmacokinetics of this murine antibody were variable and best described by nonlinear kinetics with an average t 1/2 of 20 h. Murine antibody bound extensively to all neutrophils and to a proportion of monocytes and lymphocytes. The initial 2B1 treatment induced more than 100-fold increases in circulating levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 8 and lesser rises in granulocyte-monocyte colony-stimulating factor and IFN-gamma. Brisk human anti-mouse antibody responses were induced in 14 of 15 patients. Several minor clinical responses were observed, with reductions in the thickness of chest wall disease in one patient with disseminated breast cancer. Resolution of pleural effusions and ascites, respectively, were noted in two patients with metastatic colon cancer, and one of two liver metastases resolved in a patient with metastatic colon cancer. Treatment with 2B1 BsMAb has potent immunological consequences. The maximum tolerated dose and Phase II daily dose for patients with extensive prior myelosuppressive chemotherapy was 2.5 mg/m2. Continued dose escalation is required to identify the maximally tolerated dose for patients who have been less heavily pretreated.
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PMID:Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. 755 34

Selected murine monoclonal antibodies (MAb) have been shown to inhibit relevant tumor growth in vitro and in animal models. Recently, bispecific antibodies (BsMAb) have been developed which target cytolytic effector cells via one antibody binding site and tumor antigen by the other specificity. For example, the BsMAb 2B1 possesses specificity for c-erbB-2 and Fc gamma RIII, the low affinity Fc gamma receptor expressed by polymorphonuclear leukocytes (PMN), macrophages and large granular lymphocytes (LGL). The human homologue of the rat neu oncogene, c-erbB-2, has been demonstrated to be amplified in breast, gastrointestinal, lung and ovarian carcinomas. Tumor expression of c-erbB-2 has been shown to be an important prognostic indicator in breast and ovarian carcinomas. The restricted expression of the c-erbB-2 protooncogene product in normal human tissues and the wide distribution of c-erbB-2 expression in such tumors may justify attempts to use an appropriately constructed BsMAb in clinical trials. In this report we have addressed this issue by immunohistochemically evaluating the expression of c-erbB-2 oncogene product in a variety of malignant tumors utilizing 2B1 and the anti-c-erbB-2 monovalent parent of 2B1, 520C9. Among the studied neoplasms, c-erbB-2 expression was detected in 49% of primary carcinomas stained with 520C9 and in 39% of those stained with 2B1. In the group of metastatic tumors, c-erbB-2 oncoprotein was detected in 52% of cases by 520C9 and in 41% by 2B1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunohistochemical detection of c-erbB-2 expression by neoplastic human tissue using monospecific and bispecific monoclonal antibodies. 790 24

A bispecific antibody, MDX-H210, was developed to target cytotoxic effector cells expressing Fc gamma receptor type I (Fc gammaRI, CD64) to HER2/neu-overexpressing tumor cells. HER2/neu is an appropriate target for immunotherapy due to the high level of expression of this proto-oncogene in a variety of malignancies. The expression of Fc gammaRI is limited primarily to cytotoxic immune cells, including monocytes, macrophages, and cytokine-activated polymorphonuclear (PMN) cells. Therefore, tumor cells bound with MDX-H210 can be selectively recognized by effector cells with cytotoxic potential. MDX-H210 was prepared by chemical conjugation of Fab' fragments derived from the HER2/neu-specific monoclonal antibody, 520C9, and the Fc gammaRI-specific monoclonal antibody, H22. This bispecific molecule demonstrated specific, dose-dependent, and saturable binding to both HER2/neu- and Fc gammaRI-expressing cells. A solid-phase immunoassay that demonstrated simultaneous and specific binding to both antigens was used to confirm the bispecific nature of MDX-H210. Monocytes and PMN cells mediated MDX-H210-dependent lysis of HER2/neu-overexpressing cell lines derived from breast, ovarian, and lung carcinomas. IFN-gamma treatment of monocytes enhanced antibody-dependent cellular cytotoxicity, whereas IFN-gamma and granulocyte colony-stimulating factor were required for PMN cell-mediated tumor cell lysis. In addition, MDX-H210 elicited tumor necrosis factor-alpha secretion from monocytes when cultured in the presence of HER2/neu-positive target cells. These in vitro data suggest that targeting tumor cells to Fc gammaRI with MDX-H210 may be an effective treatment for malignancies that overexpress HER2/neu. The in vivo cytotoxic potential of MDX-H210 may be enhanced by combination therapy with the cytokines granulocyte colony-stimulating factor and IFN-gamma, which up-regulate Fc gammaRI expression on cytotoxic effector cells.
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PMID:Bispecific antibody-dependent cellular cytotoxicity of HER2/neu-overexpressing tumor cells by Fc gamma receptor type I-expressing effector cells. 930 86

The class I IgG receptor (Fc gamma RI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed immunotherapy in cancer patients with the bispecific antibodies MDX-447 [humanized Fab anti-CD64 x humanized Fab anti-(epidermal growth factor receptor, EGFR)] and MDX-H210 (humanized Fab anti-DC64 x Fab anti-HER2/neu), and with the anti-CD64 monoclonal antibody (mAB) MDX-33 (H22) in the modulation of monocyte CD64 in vivo. In an ongoing phase I/II open-label trial with progressive dose escalation (1-15 mg/m2), patients with treatment refractory EGFR-positive cancers (renal cell carcinoma (RCC), head and neck, bladder, ovarian, prostate cancer and skin cancer) are treated weekly with intravenous MDX-447, with and without granulocyte-colony-stimulating factor (G-CSF). MDX-447 has been found to be immunologically active at all doses, binding to circulating monocytes and neutrophils (when given with G-CSF), causing monocytopenia and stimulating increases in circulating plasma cytokines. MDX-447 is well tolerated, the primary toxicities being fever, chills, blood pressure lability, and pain/ myalgias. Of 36 patients evaluable for response, 9 have experienced stable disease of 3-6 month's duration. The optimal dose and the maximal tolerated dose (MTD) have yet to be defined; dose escalation continues to define better the dose, toxicity, and the potential therapeutic role of this bispecific antibody. Three MDX-H210 phase II trials are currently in progress, all using the intravenous dose of 15 mg/m2 given with granulocyte/macrophage (GM-CSF). These consist of one trial each in the treatment of RCC patients, patients with prostate cancer, and colorectal cancer patients, all of whom have failed standard therapy. At the time of writing, 11 patients have been treated in these phase II trials. Four patients have demonstrated antitumor effects. Patients demonstrating responses include 2 with RCC and 2 with prostate cancer. One RCC patient has had a 54% reduction in size of a hepatic metastatic lesion and the other has had a 49% decrease in the size of a lung metastasis with simultaneous clearing of other non-measurable lung lesions. Regarding the two patients with prostate cancer, one has had a 90% reduction in serum prostate-specific antigen (PSA; 118-11 ng/ml), which has persisted for several months; the other patient with prostate has had a 70% reduction of serum PSA (872 ng/ml to 208 ng/ml) within the first month of treatment. Both patients have also demonstrated symptomatic improvement. In a completed phase I and in ongoing phase I/II clinical trials, patients with treatment-refractory HER2/neu positive cancers (breast, ovarian, colorectal, prostate) have been treated with MDX-H210, which has been given alone and in conjunction with G-CSF, GM-CSF, and interferon gamma (IFN gamma). These trials have been open-label, progressive dose-escalation (0.35-135 mg/m2) studies in which single, and more often, multiple weekly doses have been administered. MDX-H210 has been well tolerated, with untoward effects being primarily mild-to-moderate flu-like symptoms. The MTD has not yet been defined. MDX-H210 is immunologically active, binding to circulating monocytes, causing monocytopenia, as well as stimulating increases in plasma cytokine levels. Furthermore, some patients have evidence of active antitumor immunity following treatment with MDX-210. Antitumor effects have been seen in response to MDX-H210 administration; these include 1 partial, 2 minor, and 1 mixed tumor response; 15 protocol-defined stable disease responses have occurred. (ABSTRACT TRUNCATED)
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PMID:Clinical experience with CD64-directed immunotherapy. An overview. 943 76

A trispecific F(ab')3 antibody conjugate (TAC) with specificities for the Fc gamma receptor I (Fc gamma RI/CD64), the epidermal growth factor receptor (EGFR) and the HER2/neu antigen has been developed to redirect effector cell-mediated cytotoxicity against cancer cells expressing both or either of the tumor-associated antigens. The TAC was constructed in two steps using the sulfhydryl-specific cross-linker o-phenylenedimaleimide (o-PDM). In step one, a bispecific antibody was prepared by linking the Fab' fragments of mAb m22 (a murine IgG1 specific for Fc gamma RI) and mAb H425 (a humanized IgG1 antibody recognizing EGFR). The conjugation efficiency was about 60%. In the second step, the Fab' fragment of mAb 520C9, a murine IgG1 specific for HER2/neu, was coupled to the bispecific antibody made in step one. About 40% of the bispecific conjugate was derivatized to form the trispecific antibody. The purity of the TAC was more than 90% after gel filtration purification. The TAC was characterized in vitro for its ability to bind specifically to all the three antigens and to kill target cells expressing the tumor antigens. In contrast to bispecific conjugates that can only target cells expressing either of the tumor antigens, the TAC was able to bind both the antigens more efficiently in cell-binding assays and to kill tumor cells expressing EGFR and HER2/neu antigens.
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PMID:Development of a trispecific antibody conjugate that directs two distinct tumor-associated antigens to CD64 on myeloid effector cells. 1033 Nov 85

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

Macrophages represent an important effector cell for Ab-mediated tumor therapy. Previous studies have documented that cytokines can influence Fc receptor (FcR) expression and function. In this study we examined the tumoricidal activities of the type I receptors for IgG (Fc gamma RI) and the IgA FcR (Fc alpha RI) on monocyte-derived macrophages (MDM) cultured in the presence of IFN-gamma, M-CSF, or GM-CSF. Bispecific Abs were used to target a Her2/neu breast carcinoma cell line, SKBR-3, to Fc alpha RI or Fc gamma RI on MDM. Although Fc alpha RI and Fc gamma RI share a common signaling pathway contingent on association with the gamma-chain (FcR gamma subunit), a marked difference in their efficiency in mediating tumoricidal functions was seen in response to specific cytokines. M-CSF- and GM-CSF-treated MDM mediated efficient phagocytosis of SKBR-3 cells by Fc alpha RI and Fc gamma RI; however, IFN-gamma-treated MDM phagocytosed tumor cells only with the Fc gamma RI-directed bispecific Abs. Similarly, IFN-gamma-cultured MDM lysed tumor cells more efficiently via Fc gamma RI then by Fc alpha RI as measured in Ab-dependent cellular cytotoxicity assays. Conversely, GM-CSF-treated MDM mediated more efficient lysis of tumor cells via Fc alpha RI than Fc gamma RI, while M-CSF-cultured MDM were relatively less efficient in mediating Ab-dependent cellular cytotoxicity through either receptor. With the exception of IFN-gamma-mediated enhancement of Fc gamma RI expression and Fc gamma RI gamma-chain complexes, the regulation of Fc gamma RI- or Fc alpha RI-mediated activity occurred without significant change in either receptor expression or total complexes with gamma subunit. These data suggest that the efficiency of Ab-mediated tumor therapy, which depends on FcR effector cell functions, may be modified by the use of specific cytokines.
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PMID:Differential effect of cytokine treatment on Fc alpha receptor I- and Fc gamma receptor I-mediated tumor cytotoxicity by monocyte-derived macrophages. 1082 Feb 52

Unconjugated monoclonal antibodies have emerged as important therapeutic agents for selected malignancies. One mechanism by which antibodies can exert cytotoxic effects is antibody-dependent cellular cytotoxicity (ADCC). In an effort to increase the efficiency of ADCC at tumor sites, we have focused on the construction of bispecific antibodies specific for the tumor antigen HER2/neu and the Fc gamma RIII-activating receptor (CD16) found on NK cells, mononuclear phagocytes, and neutrophils. Here, we describe the production of bispecific minibodies in two distinct binding formats. The parent minibody was constructed such that the IgG1 C(H)3 constant domain serves as the oligomerization domain and is attached to an anti-CD16 and an anti-HER2/ neu single-chain Fv via 19- and 29-amino acid linkers, respectively. This molecule can be expressed in mammalian cells from a dicistronic vector and has been purified using sequential affinity purification techniques. Analysis by surface plasmon resonance shows that the bispecific minibody can bind to HER2/neu and CD16, both individually and simultaneously. Furthermore, cytotoxicity studies show that the minibody can induce significant tumor cell lysis at a concentration as low as 20 nm. A trimeric, bispecific minibody (TriBi) that binds dimerically to HER2/neu and monomerically to CD16 induces equivalent cytotoxicity at lower antibody concentrations than either the parent minibody or the corresponding single-chain dimer. Both minibody constructs are stable in mouse and human serum for up to 72 h at 37 degrees C. These minibodies have the potential to target solid tumors and promote tumor lysis by natural killer cells and mononuclear phagocytes.
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PMID:Bispecific minibodies targeting HER2/neu and CD16 exhibit improved tumor lysis when placed in a divalent tumor antigen binding format. 1547 59

Treatment of human epidermal growth factor receptor 2 (HER2/neu)-expressing breast cancer patients with a monoclonal antibody (mAb) directed against HER2/neu improves the outcome of chemotherapy. In cases in which remission is observed, antibody-dependent cell-mediated cytotoxicity (ADCC) seems to be one of the main mechanisms of anti-HER2/neu mAb action, implicating Fc gamma receptors (Fc gamma Rs) in this tumoricidal activity. In vitro and in vivo studies have revealed that anti-HER2/neu-mediated ADCC is mainly accomplished by polymorphonuclear granulocytes (PMN). C5a, a cleavage product of the complement component C5, modulates Fc gamma R expression via upregulation of activating and downregulation of inhibitory Fc gamma Rs. C5a also recruits PMNs to sites of inflammation and increases PMN survival. To enhance the recruitment and activation of C5a receptor-bearing cells into the tumor microenvironment, we developed antibody fusion proteins composed of a human IgG3 anti-HER2/neu antibody genetically fused to C5a [anti-HER2/neu IgG3-(C5a)] or to its derivative, C5a(desArg) [anti-HER2/neu IgG3-(C5a(desArg))]. Both fusion proteins were expressed, properly assembled, and secreted by murine myeloma cells, and displayed chemotactic activity on human PMN. Under comparable conditions, anti-HER2/neu IgG3-(C5a(desArg)) increased the survival of PMN more efficiently than anti-HER2/neu IgG3-(C5a) or C5a(desArg). Surprisingly, incubation of the fusion proteins with breast cancer cells that overexpress HER2/neu (SK-BR-3) induced cell death at a dose at which the anti-HER2/neu IgG3 antibody was innocuous. In the presence of human peripheral blood leukocytes as effector cells, both fusion proteins induced tumor cell death more efficiently than anti-HER2/neu IgG3. These data suggest that anti-HER2/neu IgG3-(C5a) and anti-HER2/neu IgG3-(C5a(desArg)) fusion proteins possess novel properties that could be useful in cancer immunotherapy.
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PMID:Decreased survival of human breast cancer cells expressing HER2/neu on in vitro incubation with an anti-HER2/neu antibody fused to C5a or C5a desArg. 2068 52