Reference Detail

Ref Type

Journal Article

PMID

(27550450)

Authors

Yang Y, Mandiyan S, Robinson BS, McMahon G

Title

Antitumor Properties of an IgG2-Enhanced Next-Generation MET Monoclonal Antibody That Degrades Wild-Type and Mutant MET Receptors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	76	19	2016 Oct 01	5788-5797	Cancer Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
KTN0073-IgG1	KTN0073-IgG1	0	0
KTN0073-IgG2	KTN0073-IgG2	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
KTN0073-IgG1			MET Antibody 28 MET Inhibitor 59	KTN0073-IgG1 is a chimeric anti-MET antibody comprised of a rodent variable region and human IgG1 region, which inhibits phosphorylation of MET and induces MET degradation, potentially resulting in decreased proliferation of tumor cells harboring wild-type or mutant MET (PMID: 27550450).
KTN0073-IgG2			MET Antibody 28 MET Inhibitor 59	KTN0073-IgG2 is a MET targeted antibody engineered to an IgG2 isotype, which inhibits ligand binding and induces degradation of both wild-type and mutant forms of MET, resulting in decreased tumor cell proliferation, including tumor cells harboring MET mutations and/or amplification (PMID: 27550450).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References