Antitumor effects of monoclonal antibodies affecting dimerization between ErbB family members

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Epidermal growth factor receptor (EGFR) forms homodimers and heterodimers with the other ErbB family members, ErbB2, ErbB3, and ErbB4. ErbB family members play fundamental roles in cell growth and cell survival, and they are targets for monoclonal antibody (mAb) therapy of cancer, because inappropriate ErbB activity has been implicated in several human cancer cells. However, our understanding of the pharmacological effects of mAb on tumor growth is not well developed. In this study, we examined effects of our mAb against EGFR, designated as B4G7, on growth of human non-small cell lung cancer cell lines (PC-9, PC14, and A549) as well as on that of A431 human epidermoid carcinoma cells. B4G7, but not EGF, exhibited growth-stimulatory effect upon all of these human cancer cell lines. The B4G7-stimulated cell growth was not affected by AG1478, a specific inhibitor of EGFR tyrosine kinase. Thus, the growth stimulation by B4G7 appears to be independent of the activation of EGFR tyrosine kinase. Immunoprecipitation with anti-ErbB3 antibody revealed that B4G7, but not EGF, stimulated heterodimerization between ErbB2 and ErbB3. ErbB3 was tyrosine-phosphorylated in the presence of B4G7 but not in the presence of EGF. Further, the phosphorylation of ErbB3 and B4G7-induced increase in cell growth were inhibited by AG825, a specific inhibitor of ErbB2, indicating that the ErbB2/ErbB3 dimer functions to promote cell growth in B4G7-treated cells. These findings show that ErbB family members other than EGFR affect sensitivity to EGFR-directed antibody therapies for cancer. Examination of expression levels of ErbB2 and ErbB3 in cancer cells is of importance in optimizing EGFR family-directed therapies for cancer.