B03 JNJ-61186372, an Fc Effector Enhanced EGFR/cMet Bispecific Antibody, Induces EGFR/cMet Downmodulation and Efficacy Through Monocyte and Macrophage Trogocytosis

Abstract

Small-molecule tyrosine kinase inhibitors (TKIs) have become standard of care in EGFR-mutated NSCLC, but acquired resistance invariably develops due to new mutations in EGFR and activation of compensatory pathways such as cMet. JNJ-61186372 (JNJ-372) is an anti-EGFR and cMet bispecific low-fucose antibody (huIgG1) with enhanced Fc function designed to target tumors with activated EGFR and cMet signaling through a novel mechanism of action. An ongoing first-in-human study to assess the safety and efficacy of JNJ-372 in patients with advanced, treatment-refractory NSCLC revealed JNJ-372 to have clinical activity in patients with diverse EGFR-mutated NSCLC, including tumors with EGFR mutations (Exon20, T790M, C797S) resistant to TKIs and those resistant due to MET amplification. Despite observing potent antitumor activity of JNJ-372 in EGFR mutant xenograft models, only modest antiproliferative effects were observed in NSCLC cell lines in vitro. We also found that the Fc inactive version (IgG2sigma) of the EGFR/cMet antibody was significantly impaired in its ability to inhibit tumor growth in mice compared to the Fc enhanced JNJ-372. The IgG2sigma variant also reduced the ability of the bispecific antibody to mediate downregulation of EGFR and cMet signaling. These observations suggested that the interaction of the Fc domain of the antibody with the Fcgamma receptors on innate immune cells may play a crucial role in the mechanism of action of JNJ-372. We performed a comprehensive assessment of the Fc effector functions of JNJ-372, including effects on EGFR and cMet levels, downstream signal transduction, and role in mediating antitumor activity. Using cancer cell lines in vitro, the addition of isolated human immune cells (PBMCs) significantly enhanced JNJ-372-mediated EGFR and cMet downregulation, and dose-dependent tumor cell killing. Through depletion or enrichment of specific immune cell types, we demonstrated that monocytes and/or macrophages are necessary and sufficient for JNJ-372 Fc interaction-mediated EGFR/cMet downmodulation and that macrophages are required for in vivo efficacy. Finally, through imaging studies tracking labeled JNJ-372, we visualized monocyte/macrophage-mediated trogocytosis. Collectively, these data demonstrate a novel Fc-dependent mechanism of action of JNJ-372 and support the continued clinical development in patients with aberrant EGFR and cMet signaling.