Abstract 5651: JNJ-61186372, an Fc enhanced EGFR/cMet bispecific antibody, mediates EGFR and cMet downmodulation and therapeutic efficacy preclinically through monocyte / macrophage mediated trogocytosis

Abstract

Abstract Small molecule inhibitors targeting EGFR are now standard of care in NSCLC patients harboring EGFR mutations, but acquired resistance invariably develops through secondary mutations within EGFR and/or through activation of compensatory pathways such as cMet. JNJ-61186372 (JNJ-372) is an anti-EGFR and cMet bispecific antibody with enhanced binding to immune cell Fcγ receptors, designed to target tumors with activated EGFR and cMet signaling through a distinct mechanism of action. Ongoing first-in-human study in patients with advanced, treatment refractory EGFR mutant NSCLC revealed JNJ-372 to have clinical activity in patients with diverse EGFR-mutated NSCLC, including Exon 20 mutations, TKI resistance mutations (T790M, C797S), and resistance due to MET amplification. However preclinically, despite potent anti-tumor activity in NSCLC xenograft models, only modest anti-proliferative effects were observed with JNJ-372 in cell lines in vitro. Interestingly, the addition of isolated human immune cells (PBMCs) to the in vitro assays enhanced JNJ-372-mediated EGFR and cMet downregulation, and dose-dependent tumor cell killing. Through depletion or enrichment of individual immune cell types, we demonstrated that monocytes and/or macrophages are necessary for JNJ-372 Fc interaction-mediated EGFR/cMet downmodulation. Depletion of macrophages in mice showed that they are required for JNJ-372 anti-tumor efficacy. Finally, we showed that the down-modulation of EGFR and cMet receptors occurs through monocyte or macrophage-mediated trogocytosis. Collectively, these results demonstrate a novel Fc-dependent mechanism of action for JNJ-372 and support its continued clinical development in patients with aberrant EGFR and cMet signaling. Citation Format: Smruthi Vijayaraghavan, Lorraine Lipfert, Barbara Bushey, Kristen Chevalier, Benjamin Henley, Ryan Lenhart, Marilda Beqiri, Hillary J. Millar, Kathryn Packman, Matthew V. Lorenzi, Sylvie Laquerre, Sheri Moores. JNJ-61186372, an Fc enhanced EGFR/cMet bispecific antibody, mediates EGFR and cMet downmodulation and therapeutic efficacy preclinically through monocyte / macrophage mediated trogocytosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5651.