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)

To develop an efficient strategy for the targeting of anti-tumor effector cells, we prepared bispecific antibody (BsAb) containing anti-CD3 and an anti-c-erbB-2 proto-oncogene product. The prepared BsAb specifically reacts with both c-erbB-2-positive tumor cells and CD3+ CTL. Human CD4+ helper/killer T cells, induced from peripheral-blood mononuclear cells by activation with immobilized anti-CD3 monoclonal antibody (MAb) plus IL-2, showed no significant cytotoxicity against tumor cells. However, treatment of human CD4+ helper/killer cells with the BsAb caused the induction of specific cytotoxicity against c-erbB-2-positive tumor cells. CD4+ helper/killer cells also produced significant amounts of IL-2 during co-culture with c-erbB-2-positive tumor cells in the presence of the BsAb. Moreover, by combination with the BsAb, CD4+ helper/killer cells showed a strong in vivo anti-tumor effect against c-erbB-2 transfectant or human colon-cancer cells implanted in nude mice. Our results strongly suggest that the c-erbB-2 proto-oncogene product on human tumor cells may be a good target for BsAb-directed adoptive tumor immunotherapy.
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PMID:Human c-erbB-2 proto-oncogene product as a target for bispecific-antibody-directed adoptive tumor immunotherapy. 134 16

The human genes which code for Lipocortin I and Lipocortin II, proteins that inhibit phospholipase A2 (PLA2) activity, have been regionally localized in the human genome by chromosomal in situ hybridization and segregation analysis in somatic cell hybrids using cDNA clones for Lipocortin I and II. Lipocortin I, the 35 kd substrate for the epidermal growth factor (EGF) receptor/kinase, maps to chromosome region 9q11- greater than q22. The Lipocortin II cDNA probe detects at least four independently segregating loci which map to human chromosome regions 4q21-q31.1, 9pter-q34 proximal to c-abl, 10q proximal to 10q24 and 15q21-q22 proximal to the 15q22 translocation breakpoint characteristic of acute promyelocytic leukemia (APL). Thus, Lipocortin I and one locus detected by Lipocortin II cDNA are syntenic on chromosome 9; one Lipocortin II locus is perhaps not far from the genes for EGF and IL-2 on 4q; and another of the Lipocortin II loci is on 15q, perhaps not far from the APL breakpoint.
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PMID:Chromosomal localization of the human genes for lipocortin I and lipocortin II. 296 96

We previously constructed a humanized anti-p185HER2/anti-CD3 bispecific antibody variant, BsF(ab')2 v1 which retargets the cytotoxic activity of human T cells in vitro against human breast tumor cells which overexpress the p185HER2 product of the HER2/neu (c-erbB-2) protooncogene. Subsequently we identified an improved anti-CD3 variant, v9, which binds to T cells with approx. 100-fold higher affinity than the original variant, v1. Here we demonstrate that BsF(ab')2 v9 is more potent than BsF(ab')2 v1 in stimulating the proliferation of both resting peripheral blood lymphocytes (PBL) and IL-2-activated, long-term cultured T lymphocytes (ATL). In addition, at low concentrations (0.01-1 ng/ml) BsF(ab')2 v9 is much more efficient than BsF(ab')2 v1 in directing lysis of p185HER2-overexpressing tumor cells by IL-2 activated PBL. In contrast, at higher concentration BsF(ab')2 v9 and BsF(ab')2 v1 have similar potency in retargeted cytotoxicity. At BsF(ab')2 v9 concentrations of > or = 1 ng/ml the susceptibility of p185HER2-expressing tumor cells to lysis is apparently independent of the level of p185HER2 expression. At lower concentrations of BsF(ab')2 v9 and/or lower ratios of effector to target cells the extent of lysis is reduced, in some cases improving the selectivity of lysis of high p185HER2 expressors over low expressors. Thus selection of a high affinity anti-CD3 arm is likely important in the design of BsF(ab')2 for retargeting the cytotoxicity of T cells to tumors. The dose of BsF(ab')2 v9 in any future clinical evaluation will require optimization to maximize anti-tumor efficacy whilst minimizing potential toxicity against normal tissue expressing p185HER2.
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PMID:Engineering high affinity humanized anti-p185HER2/anti-CD3 bispecific F(ab')2 for efficient lysis of p185HER2 overexpressing tumor cells. 762 74

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

Angiogenesis is a major new prognostic factor in breast cancer. Small vessels quantitatively assessed by staining with anti-CD31 antibodies correlate with lymph node involvement and are a better independent predictor of survival. There are many vascular growth factors, but predominant in primary tumors assessed by nuclease protection assays are vascular endothelial growth factor and platelet-derived endothelial cell growth factor. Acidic and basic fibroblast growth factor are also detectable. A common feature of these angiogenic factors is heparin binding, so novel analogues of suramin that can compete for heparin binding have been developed. These are more potent in vitro against endothelial cells and are less toxic in vivo, thereby giving a much better therapeutic ratio. Protein kinase C is also important in endothelial growth, as it is in carcinoma growth. Thus, a novel agent inhibiting this pathway, and inducing transforming growth factor-beta production has been assessed in a Phase I trial; this agent is bryostatin. It does not cause marrow suppression and has stimulatory effects of tumor necrosis factor-alpha and interleukin (IL)-6 production. High expression of epidermal growth factor (EGF) receptors and erbB-2 has been related to poor prognosis. EGF receptors are mainly regulated by transcription, as are some cases of high erbB-2 expression. Thus, a novel approach to gene therapy is being developed using direct tumor injection of cDNA, with a tumor specific promoter ligated to the IL-2 gene. This avoids many problems associated with targeting. Because IL-2 stimulation of cytotoxic T-cells will depend on appropriate antigen presentation, human lymphocyte antigen Class I expression was studied, as was the peptide transporter system RING4 (TAP1). Losses were found in 50% of cases, and in some cases only in lymph nodes but not primary cancers, thereby providing evidence for a role in suppressing metastasis. Thus, many new approaches to therapy are possible as a result of understanding growth factors and intracellular signaling pathways.
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PMID:Gene therapy through signal transduction pathways and angiogenic growth factors as therapeutic targets in breast cancer. 803 35

The results from the phase I/II studies of the intravenous administration of DAB486-IL-2 to patients with refractory haematological malignancies have now proven in principle the feasibility of fusion toxin therapy in man. Indeed, the cell-surface receptor-specific intoxication of neoplastic cells through the catalytic ADP-ribosylation of EF-2 is the prototype of a new class of biological response modifiers that may be generally applicable. In those circumstances where either the de novo expression or up-regulation of a cell-surface receptor can be associated with human disease [e.g. the up-regulation of the epidermal growth factor (EGF) receptor on breast cancer], it should be possible to construct genetically a DT-related/growth factor fusion protein to produce an experimental biological treatment of that malignancy. The EGF receptor-targeted fusion toxin DAB389-EGF has within the last year begun human phase I clinical trials. The pre-clinical development of DAB389-IL-7 has begun with the anticipation that this novel fusion toxin will be evaluated in the treatment of the acute leukaemias in which the IL-7R has been shown to be present.
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PMID:Diphtheria toxin-based receptor-specific chimaeric toxins as targeted therapies. 882 52

Because regional spread to lymph nodes without systemic spread is a relatively common event in squamous cell cancer of the head and neck (SCCHN), it is possible that lymphoid-related receptors or cytokines might directly impact the growth of these tumors. In the present study, we have shown by flow cytometry and Western blotting that the central lymphoid regulatory molecule, CD40, is expressed on the surface of all seven SCCHN tumor cell lines studied. Tumor cell lines also expressed epidermal growth factor (EGF) receptor, MHC class I, and CD95 (Fas) but did not uniformly express other important lymphoid regulatory molecules such as CD80, CD86, or interleukin (IL) 2 receptor components. CD40 ligation by trimeric CD40 ligand (CD40L) resulted in a 20-45% inhibition of tumor cell growth in three of seven cell lines tested. The cytokines IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-11, and IL-15 neither inhibited nor stimulated growth in any of the cell lines tested. EGF had pleiotropic effects on cell growth; it inhibited growth in two cell lines, stimulated growth in one cell line, and had no effect in four cell lines. When coligation by EGF and CD40L was studied, additive or supra-additive growth inhibition was seen in four cell lines. Three cell lines were unaffected by EGF, CD40, or coligation with both reagents. Examination of tumor tissues from 12 previously untreated patients representing a broad spectrum of patients presenting with SCCHN demonstrated CD40 expression in all 12 tumor specimens. This study supports the notion that CD40 is a regulatory molecule for the growth of SCCHN. The important role of CD40-CD40L interactions in the regulation of immune cells in the lymph node and the unique high-level expression of CD40L by these immune cells lend support to the hypothesis that this ligand/receptor pair is an important mediator of cell growth in SCCHN.
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PMID:Surface membrane-expressed CD40 is present on tumor cells from squamous cell cancer of the head and neck in vitro and in vivo and regulates cell growth in tumor cell lines. 1047 14

Although natural killer (NK) cells have been described as non-MHC-restricted, new evidence suggests that NK activity can be either up- or down-regulated after interaction with the peptide-MHC-class-I complex expressed on target cells. However, the epitope(s) recognized by NK cells have remained ill-defined. We investigated NK cell recognition of synthetic peptides representing a portion of a self-protein encoded by the HER-2/neu (HER-2) proto-oncogene and presented by HLA-A2. HER-2 nonapeptides C85, E89, and E75 were found partially to protect T2 targets from lysis by freshly isolated and interleukin-2(IL-2)-activated NK cells (either HLA-A2(+) or A2(-)). This inhibition was not solely due to changes in the level of HLA-A2 expression or conformation of serological HLA-A2 epitopes. Using single-amino-acid variants at position 1 (P1) of two HER-2 peptides, we observed that protection of targets was dependent on the sequence and the side-chain. These results suggest similarities in the mechanism of target recognition by NK and T cells. This information may be important for understanding the mechanisms of tumor escape from immunosurveillance and could help explain the aggressiveness of HER-2-overexpressing tumor cells.
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PMID:HER-2/neu peptide specificity in the recognition of HLA-A2 by natural killer cells. 1050 54

In this study the expression of epidermal growth factor receptor (EGFR) and c-erbB-2, c-erbB-3 and c-erbB-4 oncogenes were investigated in gestational trophoblastic diseases and normal first trimester placenta. Furthermore, the possibility that macrophage (IL-1 alpha, IL-1 beta, TNF) and lymphocyte (IL-2, gamma-IFN, GM-CSF) cytokines effects are mediated by changes in EGFR expression were studied. Paraffin sections of 16 cases of partial mole, 25 cases of complete mole, 10 cases of gestational choriocarcinoma and 11 cases of therapeutic abortion were studied immunohistochemically for EGFR, c-erbB-2, c-erbB-3 and c-erbB-4 proteins. The presence of EGFR mRNA was studied using in situ hybridization. JEG-3 human choriocarcinoma cells were incubated with varying concentrations of interleukin 1-alpha, interleukin 1-beta, interleukin 2, gamma-interferon, granulocyte-macrophage colony stimulating factor and tumor necrosis factor-alpha, and the expression of EGFR was measured by radioimmunoassay using a murine monoclonal antibody with specificity for EGFR. Staining for EGFR was detected immunohistochemically in all cell type in gestational trophoblastic diseases and normal placenta. The levels of expression of EGFR in choriocarcinoma and syncytiotrophoblasts and cytotrophoblasts in complete mole were significantly greater than those in syncytiotrophoblasts and cytotrophoblasts in both normal placenta and partial mole (p < 0.01, p < 0.01). The immunoreactivity of c-erbB-2 was significantly stronger in choriocarcinoma and extravillous trophoblast in complete mole than that in extravillous trophoblast in partial mole and normal placenta (p < 0.02, p < 0.01, respectively). Strong immunostaining for EGFR (p = 0.02) and c-erbB-3 (p < 0.01) in extravillous trophoblasts of complete mole was found to be significantly correlated with the development of persistent postmolar gestational trophoblastic tumor. Macrophage-derived cytokines IL-1 alpha, IL-1 beta and TNF significantly suppressed cell growth; this was associated with a significant increase in EGFR expression. The lymphocyte (IL-2, gamma-IFN, GM-CSF) cytokines had no significant effect on either EGFR expression or cell growth. These findings support the concept that cytokines may act as paracrine mediators of autocrine processes involved in choriocarcinoma cell growth regulation by modulating growth factor receptor expression. The EGFR-related family of oncogenes may be important in the pathogenesis and prognosis of gestational trophoblastic diseases.
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PMID:[The c-erbB-related oncoproteins in normal placenta and in gestational trophoblastic diseases (in vitro study)]. 1142 88


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