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

作者：Ling Liu, Wei Zeng, Mark A. Wortinger, Sheng Yan, Paul D. Cornwell, Victoria L. Peek, Jennifer R. Stephens, Jonathan W. Tetreault, Jinqi Xia, Jason R. Manro, Kelly M. Credille, Darryl Ballard, Patricia Brown‐Augsburger, Volker Wacheck, Chi-Kin Chow, Lihua Huang, Yong Wang, Irene Denning, Julian Davies, Ying Tang, Peter Vaillancourt, Jirong Lu · 发表于：Clinical Cancer Research · 年份：2014 · DOI：10.1158/1078-0432.ccr-14-0543 · 被引用次数：109 · 研究领域：Liver physiology and pathology、Cancer Cells and Metastasis、Fibroblast Growth Factor Research

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 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 ...