title: A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors.
abstract: Non-small cell lung cancers (NSCLC) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKI), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor-binding antibodies. In NSCLC tumor models driven by EGFR and/or cMet, JNJ-61186372 treatment resulted in tumor regression through inhibition of signaling/receptor downmodulation and Fc-driven effector interactions. Complete and durable regression of human lung xenograft tumors was observed with the combination of JNJ-61186372 and a third-generation EGFR TKI. Interestingly, treatment of cynomolgus monkeys with JNJ-61186372 resulted in no major toxicities, including absence of skin rash observed with other EGFR-directed agents. These results highlight the differentiated potential of JNJ-61186372 to inhibit the spectrum of mutations driving EGFR TKI resistance in NSCLC. Cancer Res; 76(13); 3942-53. ©2016 AACR.
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania. smoores@its.jnj.com.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Moores
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Chiu
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Bushey
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Kristen
authors.initials: K
authors.lastname: Chevalier
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Luistro
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Keri
authors.initials: K
authors.lastname: Dorn
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Brezski
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Peter
authors.initials: P
authors.lastname: Haytko
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kelly
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Sheng-Jiun
authors.initials: SJ
authors.lastname: Wu
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Pauline L
authors.initials: PL
authors.lastname: Martin
authors.affiliation: Genmab, Utrecht, the Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Neijssen
authors.affiliation: Genmab, Utrecht, the Netherlands. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
authors.affiliation: Genmab, Utrecht, the Netherlands.
authors.forename: Janine
authors.initials: J
authors.lastname: Schuurman
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Attar
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Laquerre
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Lorenzi
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: G Mark
authors.initials: GM
authors.lastname: Anderson
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met