UNIPROT:P04626 - FACTA Search

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)

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

Human CD4+ T cells activated with staphylococcal enterotoxin A (SEA) were fractionated by Percoll discontinuous density gradient centrifugation to enrich SEA-reactive CD4+ T cells. The SEA-reactive CD4+ T cells showed significant cytotoxicity, so-called superantigen-dependent cell-mediated cytotoxicity, against SEA-coated class II-positive tumor cells. During lysis of SEA-coated tumor cells, SEA-reactive CD4+ T cells produced high levels of IL-2 and IFN-gamma but not IL-4 in an Ag-specific manner. The skewing of human CD4+ T cells to Th1-type helper/killer T cells was also demonstrated when SEA-reactive CD4+V beta 5.3+ clonal T cells were cultured with SEA, but not with PHA or OKT3 mAb. Interestingly, the generation of SEA-reactive helper/killer T cells was negatively regulated by IL-4, but up-regulated by IL-12. The SEA-reactive CD4+ helper/killer T cells were able to generate from PBMC of tumor patients and could be expanded to 10(9) levels in a 7-day culture. The SEA-reactive CD4+ helper/killer T cells were specifically targeted to c-erbB-2 positive human colon cancer cells using SEA-conjugated-anti-c-erbB-2 mAb. These results initially demonstrated that SEA-activated human CD4+ T cells are a Th1 type of Th cell that has both helper and killer functions which may be useful for adoptive tumor immunotherapy in combination with SEA-conjugated antitumor mAb.
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PMID:Superantigen-induced human CD4+ helper/killer T cell phenomenon. Selective induction of Th1 helper/killer T cells and application to tumor immunotherapy. 783 62

It is an important issues to investigate an efficient methods to induce antitumor effector T cells from peripheral blood lymphocytes of tumor patients for the development of a novel tumor immunotherapy. We established a large scale culture system of human CD4+ helper/killer T cells which have both helper and killer functions. Targeting of CD4+ helper/killer T cells to tumor using anti-CD3 x anti-c-erbB-2 mAb caused the lysis of tumor and triggering of IL-2 production. It was also demonstrated that culture of human CD4+ T cells with staphylococcal enterotoxin A (SEA) or IL-12 caused a selective induction of Th1 type of CD4+ helper/killer T cells. IL-12 also revealed a novel effect on CD8+CTL functions. Culture of CD8+ T cells with IL-12 resulted in the augmentation of IFN-gamma production and cytotoxicity. Moreover, culture of tumor-infiltrating lymphocytes with IL-12 caused a marked enhancement of CD8+CTL against autologous tumor cells. These findings suggest that IL-12 will become a useful cytokine for the tumor immunotherapy. In this paper, we will discuss the key role of CD4+ T cells for the induction of antitumor immunity in tumor-bearing host.
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PMID:[An efficient methods for the induction of human antitumor effector CD4+ and CD8+ T cells: their application to tumor immunotherapy]. 787 96

In vitro, monocyte-derived macrophages (MDM) are capable of efficient antibody-mediated phagocytosis of human nucleated tumor cells. These MDM express on their cell surface all three classes of Fc receptors for IgG (Fc gamma R). Fc gamma R specificity for murine antibody isotype allowed us to examine the phagocytic role of Fc gamma RII on control and gamma-interferon (IFN-gamma)-primed MDM. Monoclonal antibody 520C9 (IgG1) mediates phagocytosis through Fc gamma RII. This monoclonal antibody is directed against the HER-2/neu protooncogene product overexpressed on a variety of adenocarcinomas including the breast carcinoma cell line SK-BR-3. Our results showed that IFN-gamma treatment of differentiated MDM (days 8-12 in culture) inhibited Fc gamma RII-mediated phagocytosis in a dose-dependent manner with negative effects noted at doses as low as 0.1 units/ml. The percentage reduction in antibody-mediated phagocytosis observed following IFN-gamma priming (40 units/ml for 18 h) ranged from 23-89% of control. The inhibitory effect was evident when exposure to IFN-gamma was transient. Fc gamma RII expression was not altered by IFN-gamma treatment. In our model, IFN-gamma did not up-regulate or down-regulate HER-2/neu protein expression on our targets or affect the level of CD14 antigen expression on our MDM. Although IFN-gamma is a potent activator of monocytes/macrophages and can enhance certain tumoricidal mechanisms, our data show that antibody-dependent phagocytosis through the type II Fc receptor is inhibited by IFN-gamma priming. Nonspecific phagocytosis was not affected.
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PMID:Gamma-interferon inhibits Fc receptor II-mediated phagocytosis of tumor cells by human macrophages. 790 75

A quantitative method of polymerase chain reaction (PCR) using both digoxigenin and radioactive labelled probes has been used for the detection of the c-erbB-2 proto-oncogene amplification in breast carcinomas with formalin-fixed paraffin-embedded tissue sections. c-erbB-2 proto-oncogene amplification has been demonstrated in 14 infiltrating ductal carcinomas. The technique consisted of the co-amplification of c-erbB-2 and IFN-gamma (interferon-gamma) genes. The latter was considered as a single copy gene per genome-equivalent. The aim of this study was to compare two quantitative PCR techniques based on the incorporation of either digoxigenin-11-dUTP or 32P-dCTP, during amplification. For the colorigenic method, using the Dig system, after electrophoresis and transfer, the specific bands were revealed with a chromogenic substrate of phosphatase. Their intensity estimated by scanning photometry following blot transparisation. After electrophoresis, the radioactive gel was submitted to radioautography and the band intensities evaluated by scanning spectrophotometry. For the 14 samples, a good agreement between both methods was noted. The colorigenic method is a valuable alternative to radiolabelling due to: i) time saving, ii) reagent conservation, iii) safe manipulation and iv) sensitivity of the same order for both methods.
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PMID:Determination of amplification level of the c-erbB-2 proto-oncogene in human breast carcinomas: a comparative study between non-radioactive and radioactive labelling. 859 75

We have developed an in vitro model to study mechanisms by which ovarian tumor cells that over-express the HER-2/neu proto-oncogene escape recognition by TCD8+. Nine tumor-specific, HLA A2-restricted TCD8+ clones were isolated from 2 ovarian tumor-specific TCD8+ lines derived from tumor-infiltrating or -associated lymphocytes. Of these, 2 clones recognized the previously defined HER-2/neu epitope E75 (a.a. 369-377) and one recognized the C85 epitope (a.a. 971-979), whereas the specificity of the remaining 6 clones was unknown. Three different tumor escape variants (EVC8, EVC22 and EVC36) were produced by co-culturing an ovarian tumor line over-expressing HER-2/neu with these autologous TCD8+ clones. Cell surface expression of HLA A2 was markedly decreased on all 3 escape variants, relative to the parental tumor line, while no significant decrease in their expression of the HER-2/neu, ICAM-1 or LFA-3 molecules was found. There was a correlation between the level of tumor-specific recognition and HLA A2 expression among the tumor clones isolated from 2 of the escape variants (EVC8 and EVC36). In contrast, high HLA A2-expressing tumor clones isolated from the EVC22 variant, or EVC22 which had regained high HLA A2 expression through IFN-gamma treatment, were not recognized by the HER-2/neu-specific TCD8+ clone C-22. No mutations were found in the cDNA or the genomic DNA derived from the PCR product corresponding to a 496 bp fragment including the region coding for the E75 epitope of the HER2/neu gene in the EVC22 variant. Collectively, this in vitro model underlines the importance of decreased expression of the HLA restriction element for escape from tumor-specific TCD8+ but also demonstrates that additional mechanisms exist.
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PMID:Mechanisms of escape from CD8+ T-cell clones specific for the HER-2/neu proto-oncogene expressed in ovarian carcinomas: related and unrelated to decreased MHC class 1 expression. 898 99

The induction of prostaglandin G/H synthase (PGHS; prostaglandin endoperoxide synthase, cyclooxygenase) by proinflammatory cytokines accounts, at least in part, for the altered eicosanoid biosynthesis in inflammatory diseases. In secondary cultures of normal human bronchial epithelial cells (NHBECs), interferon-gamma (IFN-gamma, 10 ng/ml for 24 h) increased the amount of prostaglandin E2 (PGE2) released in response to stimulation with exogenous arachidonic acid (5 microM). The enhanced production of PGE2 reflected the upregulation of PGHS-2 as indicated by enhanced expression of PGHS-2 RNA and increased recovery of PGHS-2 protein in NHBECs. IFN-gamma did not alter the production of PGE2 in A549 cells (a human lung adenocarcinoma cell line) or 6-keto-PGF1alpha in human umbilical vein endothelial cells (HUVECs), although prostaglandin release and/or the expression of PGHS-2 RNA in these cell lines was upregulated by other proinflammatory cytokines. Induction of PGHS-2 RNA in IFN-gamma-treated NHBECs, which peaked at 24 h, suggested the presence of an intermediary substance regulating the expression of PGHS-2. When the binding between the epidermal growth factor (EGF) receptor and its ligands was disrupted by a neutralizing antibody (LA-1), IFN-gamma failed to upregulate the release of PGE2 and the expression of PGHS-2 RNA in NHBECs. Furthermore, IFN-gamma induced the expression of RNAs for a number of ligands at the EGF receptor TGF-alpha; heparin-binding EGF-like growth factor (HB-EGF); and amphiregulin in NHBECs, and when administered exogenously, these ligands increased PGE2 release from NHBECs. Heparin at the concentration that neutralized the function of amphiregulin, or antibodies against TGFalpha or HB-EGF also reduced the release of PGE2 from IFN-gamma-stimulated NHBECs. These data are consistent with the presence of an autocrine growth factor/EGF receptor loop regulating PGHS-2 expression and PGE2 synthesis in bronchial epithelial cells.
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PMID:Interferon gamma induces prostaglandin G/H synthase-2 through an autocrine loop via the epidermal growth factor receptor in human bronchial epithelial cells. 906 64

Identifying target antigens for tumor-reactive T cells is important for understanding the mechanisms of tumor escape and developing novel anticancer therapies. To date, mainly CTL responses from tumor infiltrating associated lymphocytes (TIL/TAL) to peptide antigens have been investigated in ovarian cancer. In the present study, the ability of self-peptides derived from HER-2/neu proto-oncogene product (HER-2) to stimulate proliferation of PBMC from healthy donors and ovarian cancer patients has been assessed. Peptide sequences from HER-2 containing anchors for major human MHC-class II molecules have been identified. These peptides induced proliferative and cytokine responses at higher frequency in healthy donors than ovarian cancer patients. Four HER-2 peptides corresponding to positions: 396-406, 474-487, 777-789, and 884-899 were able to stimulate proliferation of a larger number of healthy donors than three other distinct HER-2 peptides 449-464, 975-987 and 1086-1098. The pattern of responses of twenty five ovarian cancer patients was different from that in healthy donors. T cell lines were developed by stimulation with peptides from PBMC of an ovarian cancer patient who showed a stable response to all four HER-2 peptides for over six months. Each T cell line was different in its ability to secrete IFN-gamma and IL-10. These results demonstrate (a) that self-peptides from HER-2 can stimulate expansion of T cells in both healthy donors and ovarian cancer patients, and (b) the ability of different peptides to stimulate secretion of different cytokines from lymphocytes of ovarian cancer patients. These results may be important for understanding the mechanisms of tolerance and autoimmunity in human cancers.
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PMID:Existent proliferative responses of peripheral blood mononuclear cells from healthy donors and ovarian cancer patients to HER-2 peptides. 906 29

Previous studies have characterized the reactivity of CD8+ CTLs with ovarian and breast cancer. There is little information about the antigens and epitopes recognized by CD4+ T cells in these patients. In this study, we analyzed the ability of T cells from peripheral blood mononuclear cells of breast cancer patients to recognize HER-2/neu (HER-2) peptides. We found that 13 of 18 patients responded by proliferation to at least one of the HER-2 peptides tested. Of these peptides, one designated G89 (HER-2: 777-789) was recognized by T cells from 10 patients. Seven of nine responding patients were HLA-DR4+, suggesting that this peptide is recognized preferentially in association with HLA-DR4. Analysis of the specificity and restriction of the cytokine responses to G89 by G89-stimulated T cells revealed that these cells secreted significantly higher levels of IFN-gamma than interleukin 4 and interleukin 10, suggesting priming for a Th0-T helper 1 response. The same pattern of cytokine responses was observed to the intracellular domain of HER-2 protein, suggesting that G89-stimulated T cells recognized epitopes of the HER-2 protein in association with HLA-DR4. Because HLA-DR4 is present in 25% of humans, characterization of MHC class II-restricted epitopes inducing Th0-T helper 1 responses may provide a basis for the development of multivalent HER-2-based vaccines against breast and ovarian cancer.
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PMID:Proliferative and cytokine responses to class II HER-2/neu-associated peptides in breast cancer patients. 971 33

The oncogene HER-2/neu is genetically amplified and overexpressed in a large number of human adenocarcinomas and has been implicated in the tumorigenic phenotype. Although it is a nonmutated self-protein, it is barely detectable in adult tissues, and immune responses toward it have been described in a number of patients. It is, thus, an attractive candidate antigen for the immunotherapy of cancer patients. HLA-A2+ patients with metastatic breast, ovarian, or colorectal adenocarcinomas that overexpressed HER-2/neu were immunized with the HLA-A2-binding epitope p369-377 (p369). Patients were treated by repeated immunization with 1 mg of p369 in Freund's incomplete adjuvant every 3 weeks. Peripheral blood mononuclear cells were collected prior to immunization and following two and four immunizations and were stimulated in vitro with peptide and assayed for peptide and tumor recognition. In three of four patients, peptide-specific CTLs were detected in post- but not preimmunization blood. These CTLs recognized peptide-pulsed target cells at peptide concentrations of > or =1 ng/ml yet failed to react with a panel of HLA-A2+ HER-2/neu+ tumor lines. In addition, infecting HLA-A2+ cells with recombinant vaccinia virus encoding HER-2/neu or up-regulating HLA-A2 with IFN-gamma in HER-2/neu+ cells also failed to confer reactivity by p369-reactive T-cells. A T-cell response to the HLA-A2 binding epitope p369 can be easily generated by immunizing patients with peptide in Freund's incomplete adjuvant. However, the CTLs failed to react with HER-2/neu+ tumor cells. Further studies are needed to determine whether and how HER-2 might serve as an antigen for tumor immunotherapy.
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PMID:Immunization with a peptide epitope (p369-377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu+ tumors. 980 97

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