Serotherapy provides an appealing approach to eliminate cancer cells that remain after conventional treatment. Murine monoclonal antibodies against certain epitopes on the extracellular domain of p185 (c-erbB-2) can inhibit growth of ovarian and breast carcinoma cells that overexpress this transmembrane tyrosine kinase growth factor receptor. During the present grant period we have shown that antibody mediated inhibition of anchorage independent growth requires the tyrosine kinase region of p185 (c-erbB-2). Growth inhibition has correlated with increased tyrosine phosphorylation of p185 (c-erbB-2) and phospholipase C gamma, decreased levels of diacylglycerol and late phosphorylation of intracellular substrates on serine and threonine residues. Both antibody and heregulin, the HER-2/neu (c-erbB-2) ligand, have inhibited growth, enhanced invasiveness and increased tyrosine phosphorylation of p185 (c-erbB-2) and phospholipase C gamma in cells that overexpress c- erbB-2. In continued studies we will further explore the mechanism of antibody mediated changes in growth and differentiation, testing the novel hypothesis that antibodies are mimicing, rather than antagonizing ligand activity. To provide more potent inhibition of tumor growth, ricin A chain (RTA) and radionuclide conjugates have been prepared with antibodies against the extracellular domain of p185 (c-erbB-2). Up to 99.99% of clonogenic tumor cells that overexpress p185 (c-erbB-2) can be eliminated by RTA immunotoxins. Significant inhibition of human ovarian cancer heterografts has been achieved by treatment with these immunotoxins. Synergistic cytotoxicity has been observed ex vivo using immunotoxins reactive with p185 (c-erbB-2) and p170 (EGFR), receptors that are coexpressed by ovarian and breast cancers. Synergistic cytotoxicity has also been exerted with irradiation and anti-p185 (c- erbB-2) immunotoxin. In future studies we will explore the anti-tumor activity of toxin and radionuclide conjugates directed against p185 (c- erbB-2) and p170 (EGFR), testing the novel hypothesis that synergistic cytotoxicity will be observed when RTA immunotoxins inhibit protein synthesis and block induction of enzymes required for prevention or repair of radiation induced damage to DNA.
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