LY2875358, a Neutralizing and Internalizing Anti-MET Bivalent Antibody, Inhibits HGF-Dependent and HGF-Independent MET Activation and Tumor Growth

Abstract

Purpose: 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.Experimental Design/Results: Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGFdependent 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 HGFresponsive 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 (METamplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody.Conclusions: 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. Clin Cancer Res; 20(23); 6059-70. Ó2014 AACR.

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer

“…The starting dose and the dose range were selected based on toxicology results and modeling of PK and PD data from nonclinical studies (11). Emibetuzumab was administered intravenously over 90 minutes at the 20-to 700-mg dose levels and over 150 minutes at the 1,400-and 2,000-mg dose levels.…”

“…Emibetuzumab blocks HGF-dependent signaling by binding to MET, and also blocks independent signaling of the MET receptor by subsequent internalization and degradation. Pharmacokinetic/pharmacodynamic modeling and simulation suggest that emibetuzumab exposures achieved by 700 mg every 2 weeks (Q2W) or higher are expected to prevent MET signaling, reduce expression of MET, and inhibit MET-driven growth of tumors based on preclinical studies (11). Three patients treated in the biologically efficacious dose range of 700 to 2,000 mg emibetuzumab 700 mg Q2W or greater demonstrated partial response according to Response Evaluation Criteria in Solid Tumors.…”

“…Administration of a single dose of emibetuzumab resulted in continuous reduction of MET protein expression for 14 days in mouse xenografts. Emibetuzumab demonstrated dose-dependent, single-agent activity in various MET-expressing tumor models, and additive effects were observed in combination with erlotinib for reducing tumor volume in lung cancer mouse xenograft models (11).…”

“…Moreover, emibetuzumab triggers MET receptor internalization and downregulation of total membrane MET expression, leading to inhibition of ligand-independent activation of MET signaling, as well (11).…”

Targeting MET in Cancer: Obstacles and Potentials

“…In addition to blocking HGF-MET binding and HGF-induced MET phosphorylation and cell proliferation, 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 HGFindependent (MET-amplified) xenograft tumor models [43]. Given its unique design and mechanism of action, LY2875358 has a potential to be successful.…”