title: Antitumor Properties of an IgG2-Enhanced Next-Generation MET Monoclonal Antibody That Degrades Wild-Type and Mutant MET Receptors.
abstract: A sound rationale exists for antibody targeting of the MET receptor tyrosine kinase, but therapeutic agents that can broadly block HGF ligand binding and exon 14-mutated or amplified MET to induce receptor degradation have yet to be reported. Here we report the identification of several MET monoclonal antibodies (mAb) that block MET-dependent signaling and tumor growth. In particular, the MET mAb KTN0073 and KTN0074 bind the Sema/PSI domain, at overlapping but distinct epitopes, preventing HGF interaction with MET and triggering receptor ubiquitination and degradation. Notably, both mAbs also triggered degradation of oncogenic MET exon 14 mutants, which propagate more durable MET signals due to a defect in receptor degradation. Mechanistic investigations showed that both mAbs engaged a pathway distinct from HGF-induced receptor degradation and protease-mediated shedding, independently of signaling driven by the exon 14-encoded sequences in the intracellular juxtamembrane region of the MET receptor. Grafting the mAb variable regions onto the IgG2 constant region dramatically enhanced the tumor inhibitory activities of KTN0073 but not KTN0074, suggesting a specific influence of antibody isotype of the epitopes for these two MET mAbs. Overall, our results highlight KTN0073 as a novel IgG2-based MET mAb that acts through exon 14-independent mechanisms to degrade the MET receptor, potentially offering a therapeutic tool to treat a broader range of human tumors where MET is exon 14 mutated or amplified. Cancer Res; 76(19); 5788-97. ©2016 AACR.
authors.affiliation: Kolltan Pharmaceuticals, New Haven, Connecticut. y.yang@kolltan.com jerry.mcmahon@kolltan.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Kolltan Pharmaceuticals, New Haven, Connecticut.
authors.forename: Sreekala
authors.initials: S
authors.lastname: Mandiyan
authors.affiliation: Kolltan Pharmaceuticals, New Haven, Connecticut.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Robinson
authors.affiliation: Kolltan Pharmaceuticals, New Haven, Connecticut. y.yang@kolltan.com jerry.mcmahon@kolltan.com.
authors.forename: Gerald
authors.initials: G
authors.lastname: McMahon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met