American Association for Cancer Research
00085472can152833-sup-156835_1_supp_3347203_w28t40.ppt (174.5 kB)

Supplemental Figure S3 from A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor–Resistant Lung Tumors

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posted on 2023-03-30, 23:21 authored by Sheri L. Moores, Mark L. Chiu, Barbara S. Bushey, Kristen Chevalier, Leopoldo Luistro, Keri Dorn, Randall J. Brezski, Peter Haytko, Thomas Kelly, Sheng-Jiun Wu, Pauline L. Martin, Joost Neijssen, Paul W.H.I. Parren, Janine Schuurman, Ricardo M. Attar, Sylvie Laquerre, Matthew V. Lorenzi, G. Mark Anderson

Effect of Crizotinib on H1975 and H1975-HGF Xenograft Tumors



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.

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