title: Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.
abstract: Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers acquire resistance to EGFR tyrosine kinase inhibitors through multiple mechanisms including c-Met receptor 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-Met pathway activation. JNJ-61186372 was engineered with low fucosylation (<10 %), resulting in enhanced antibody-dependent cell-mediated cytotoxicity and FcγRIIIa binding. In vitro and in vivo studies with the single-arm EGFR or c-Met versions 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-Met single-arm antibody reduced tumor growth inhibition compared to treatment with JNJ-61186372, suggesting that the Fc function of JNJ-61186372 is essential for maximal tumor inhibition. Moreover in this same model, downregulation of both EGFR and c-Met receptors was observed upon treatment with Fc-competent JNJ-61186372, suggesting that the Fc interactions are necessary for down-modulation of the receptors in vivo and for efficacy. These Fc-mediated activities, in combination with inhibition of both the EGFR and c-Met signaling pathways, highlight the multiple mechanisms by which JNJ-61186372 combats therapeutic resistance in EGFR mutant patients.
authors: a Biologics Research, Janssen Research and Development, LLC , Spring House , PA , USA.
authors: Katharine D
authors: KD
authors: Grugan
authors: a Biologics Research, Janssen Research and Development, LLC , Spring House , PA , USA.
authors: Keri
authors: K
authors: Dorn
authors: a Biologics Research, Janssen Research and Development, LLC , Spring House , PA , USA.
authors: Stephen W
authors: SW
authors: Jarantow
authors: b Oncology, Janssen Research and Development, LLC , Spring House , PA , USA.
authors: Barbara S
authors: BS
authors: Bushey
authors: a Biologics Research, Janssen Research and Development, LLC , Spring House , PA , USA.
authors: Jose R
authors: JR
authors: Pardinas
authors: b Oncology, Janssen Research and Development, LLC , Spring House , PA , USA.
authors: Sylvie
authors: S
authors: Laquerre
authors: b Oncology, Janssen Research and Development, LLC , Spring House , PA , USA.
authors: Sheri L
authors: SL
authors: Moores
authors: a Biologics Research, Janssen Research and Development, LLC , Spring House , PA , USA.
authors: Mark L
authors: ML
authors: Chiu
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D008175:Lung Neoplasms; D051379:Mice; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D007141:Immunoglobulin Fc Fragments; C000718215:amivantamab; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: Antibody-dependent cell mediated cytotoxicity; EGFR; Fc engineering; antibody-dependent cell mediated phagocytosis; bispecific; c-Met; hemi-afucosylated; low fucose