Monoclonal antibodies to the EGF receptor act as betacellulin antagonists

Betacellulin (BTC), a recently discovered member of the EGF family that is produced by certain tumour cells, is thought to be involved in autocrine growth by activating the EGF receptor (EGFR). We have investigated whether monoclonal antibodies (mAbs) to the EGFR which act as EGF, TGF alpha and HB-EGF antagonists could also be effective as BTC antagonists by blocking its binding to the EGFR. We report that the binding of 125I-BTC to a range of tumour cells expressing the EGFR was inhibited by rat mAbs that bound to three distinct epitopes on the extracellular domain of the EGFR. We show that one of these mAbs (ICR62) also prevents activation of the EGFR by betacellulin as evidenced by reversal of the effects on the growth of human fibroblasts and the head and neck carcinoma cell line HN5 and by inhibition of receptor phosphorylation in HN5 cells. We conclude that mAbs such as ICR62 have potential for use as therapeutic agents by blocking betacellulin-induced growth of tumours which over-express the EGFR.