Abstract 3835: An anti-MET IgG2 monoclonal antibody degrades both wild-type and exon 14 mutant MET receptor tyrosine kinase through a novel exon 14-independent mechanism and inhibits tumor growth

Abstract

Abstract MET gene amplification and exon 14 mutations have been reported and implicated as oncogenic drivers in several types of cancer representing approximately 5-7% of NSCLC, 4-10% of gastric cancer, and 5-10% of colon cancers. Preclinical research and clinical data derived from patients with tumors containing MET gene amplification and exon 14 mutations showed significant growth inhibition and meaningful clinical benefit after treatment with MET-targeting tyrosine kinase inhibitors (TKIs), supporting the hypothesis that MET gene amplification and exon 14 mutations are actionable biomarkers. We have identified several anti-MET monoclonal antibodies that block MET-dependent signaling and tumor growth through: (1) binding to the Sema/PSI domain, (2) preventing HGF interaction with MET and (3) inducing receptor ubiqutination and degradation. One of the anti-MET antibodies, KTN0073, induces potent degradation of oncogenic exon 14 mutant MET, which has been reported to propagate prolonged MET signaling due to a defect in receptor degradation. Our data suggest that KTN0073 engages a pathway different from HGF-induced receptor degradation and protease-mediated shedding, which is independent of the 47 amino acids that are encoded by exon 14 in the intracellular juxtamembrane region and only partially inhibited by the TKI crizotinib. In summary, we report the use of an anti-MET monoclonal antibody to elucidate an exon 14-independent mechanism of MET degradation that could provide a novel way to design anti-MET therapeutics to inhibit growth of human tumors that are driven by HGF, MET amplification and exon 14 mutations. Based on this work, KTN0073-IgG2 anti-MET antibody has been humanized for further preclinical development to explore its potential as a therapeutic for the treatment of human MET expressing cancers. Citation Format: Brett S. Robinson, Sreekala Mandiyan, Gerald McMahon, Yan Yang. An anti-MET IgG2 monoclonal antibody degrades both wild-type and exon 14 mutant MET receptor tyrosine kinase through a novel exon 14-independent mechanism and inhibits tumor growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3835.