LIGAND-LIKE EFFECTS INDUCED BY ANTI-C-ERBB-2 ANTIBODIES DO NOT CORRELATE WITH AND ARE NOT REQUIRED FOR GROWTH-INHIBITION OF HUMAN CARCINOMA-CELLS

The c-erbB-2 gene encodes a M(r) 185,000 tyrosine kinase receptor (p18 5) with extensive homology to the epidermal growth factor receptor. We have conducted mechanistic studies with several anti-pl85 monoclonal antibodies (TAb 250,-255, -257, -260, and -263) directed against the e xtracellular domain of p185 utilizing the SKBR-3, BT-474, and SKOV-3 c ancer cell lines. Several of these antibodies exhibited ligand-mimicki ng properties: they induced tyrosine phosphorylation of p185; increase d the catalytic activity of the receptor substrate phospholipase C-gam ma 1; exhibited time- and pH-dependent internalization; induced recept or down-regulation; and increased the turnover of the p185 protein Del ta 3-fold. However, there was not a universal correlation between the antibody-mediated ligand-like effects and growth inhibition. TAb 250 i nhibited BT-474 cells but did not alter p185 phosphotyrosine content o r increase receptor turnover in these cells. TAb 260 increased p185 pr otein turnover but did not affect proliferation of the SKOV-3 cell lin e. Furthermore, blockade of TAb 250-induced receptor phosphorylation w ith the tyrosine kinase inhibitor tyrphostin 50864-2 did not abrogate TAb 250-mediated growth inhibition of SKBR-3 cells. These data suggest that ligand-like effects mediated by p185 antibodies are not critical for the growth inhibition of c-erbB-2-overexpressing carcinoma cells.