Reference Detail

Ref Type

Journal Article

PMID

(25231402)

Authors

Liu L, Zeng W, Wortinger MA, Yan SB, Cornwell P, Peek VL, Stephens JR, Tetreault JW, Xia J, Manro JR, Credille KM, Ballard DW, Brown-Augsburger P, Wacheck V, Chow CK, Huang L, Wang Y, Denning I, Davies J, Tang Y, Vaillancourt P, Lu J

Title

LY2875358, a neutralizing and internalizing anti-MET bivalent antibody, inhibits HGF-dependent and HGF-independent MET activation and tumor growth.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	20	23	2014 Dec 01	6059-70	Clin Cancer Res

URL

Abstract Text

MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms.Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody.LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies.

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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
Emibetuzumab	Emibetuzumab	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Emibetuzumab		LY2875358	MET Antibody 28 MET Inhibitor 59	Emibetuzumab (LY2875358) is MET-targeted antibody, which inhibits binding of the MET ligand HGF and promotes internalization and downregulation of MET, resulting in decreased HGF-dependent and HGF-independent signaling and potentially leading to decreased growth of MET-expressing tumors (PMID: 27803065, PMID: 25231402, PMID: 31622732).

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