Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells

ABSTRACTEpidermal growth factor receptor (EGFR) mutant non-small cell lung cancers acquire resistance to EGFR tyrosine kinase inhibitors through multiple mechanisms including c-Metreceptor pathway activation. We generated a bispecific antibody targeting EGFR and c-Met(JNJ-61186372) demonstrating anti-tumor activity in wild-type and mutant EGFR settings with c-Metpathway activation. JNJ-61186372 was engineered with low fucosylation(<10 %), resulting in enhanced antibody-dependent cell-mediated cytotoxicityand FcγRIIIa binding. In vitro and in vivo studies with the single-arm EGFR or c-Metversions of JNJ-61186372 identified that the Fc-activity of JNJ-61186372 is mediated by binding of the anti-EGFR arm and required for inhibition of EGFR-driven tumor cells. In a tumor model driven by both EGFR and c-Met, treatment with Fc-silent JNJ-61186372 or with c-Metsingle-arm antibody reduced tumor growth inhibition compared to treatment with JNJ-61186372, suggesting that the Fc function of JNJ-61186372 is ess...