Biological studies and potential therapeutic applications of monoclonal antibodies and small molecules reactive with the neu/c-erbB-2 protein.

The overexpression of the growth factor receptor p185neu/c-erbB-2 has been observed in a number of human adenocarcinomas and is mechanistically linked to neoplastic growth. Monoclonal antibodies raised against extracellular domains of the p185neu/c-erbB-2 receptor oncoprotein have been utilized to inhibit the pathway of neu-induced tumor development. Our laboratory has demonstrated a direct effect of anti-p185neu/c-erbB-2 antibodies which requires receptor ligation. This induced aggregation causes the downmodulation of cell-surface expression and eventual degradation of p185neu/c-erbB-2 protein. In cells transformed by the neu oncogene, the result of antibody-induced p185neu/c-erbB-2 receptor modulation is the reversion of the malignant phenotype. We are exploiting the direct efficacy of this monoclonal antibody by developing small molecules (peptides and organic mimietics) based on anti-p185neu/c-erbB-2 antibody structure that can mediate similar receptor binding and biological effects.