Abstract 5465: LY2875358, a bivalent MET antibody with anti-tumor activity through blocking HGF as well as inducing degradation of MET, differentiates from a one-armed 5D5 MET antibody.

Abstract

MET is involved in many mechanisms of cancer proliferation and metastasis. Inappropriate activation of MET can be induced by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional up-regulation, or by HGF-dependent autocrine or paracrine mechanisms. LY2875358 is a novel humanized bivalent MET antibody currently in phase I clinical testing (trial NCT01287546). LY2875358 has high neutralization and internalization activities against MET for inhibiting HGF-dependent and HGF-independent MET pathway activation and tumor growth. In HGF-dependent MET activation, LY2875358 blocks HGF binding to MET, HGF-induced MET phosphorylation and tumor growth both in cell culture and in mouse xenograft models, resembling activities of a humanized one-armed 5D5 MET antibody (monovalent antibody similar to Onartuzumab). In tumors with HGF-independent MET activation through MET gene amplification, LY2875358 induces internalization and degradation of MET, which results in decreased pMET and total MET, inhibition of cell proliferation and tumor growth in MKN45 and SNU5 gastric tumor lines and EBC-1 and H1993 NSCLC tumor lines. Moreover, LY2875358 enhances antitumor activity in combination with cisplatin or 5-FU in vitro and in vivo in MET amplified tumor cells. However, under the same ligand-independent conditions, the one-armed 5D5 antibody did not have anti-tumor activities. When HGF is added to tumor cells with high MET gene amplification, LY2875358 decreases cell proliferation, while the one-armed 5D5 antibody does not. In contrast to other bivalent MET antibodies, LY2875358 has no or otherwise negligible agonist activity and does not stimulate biological activities such as cell proliferation, scattering, invasion, tubulogenesis, apoptosis protection or angiogenesis in various HGF responsive cells. These findings indicate that LY2875358 has a different mechanism of action from the humanized one-armed 5D5 MET antibody. LY2875358 may be a promising therapy for treatment of patients whose tumors are driven by HGF-dependent and HGF-independent MET activation. Citation Format: Wei Zeng, Victoria Peek, Mark Wortinger, Jonathan Tetreault, Jinqi Xia, Jennifer Stephens, Kelly Credille, Darryl Ballard, Trish Brown-Augsburger, Jirong Lu, Chi-Kin Chow, Peter Vaillancourt, Ying Tang, Sau-Chi B. Yan, Ling Liu. LY2875358, a bivalent MET antibody with anti-tumor activity through blocking HGF as well as inducing degradation of MET, differentiates from a one-armed 5D5 MET antibody. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5465. doi:10.1158/1538-7445.AM2013-5465

MET/HGF targeted drugs as potential therapeutic strategies in non-small cell lung cancer

“…LY2875358 has demonstrated significant antitumor activity in preclinical studies, even against MET mutants that did not respond to onartuzumab [196][197][198]. A phase II study is currently evaluating the combination of LY2875358 with erlotinib as first-line treatment for patients with advanced NSCLC and activating EGFR mutations (NCT01897480).…”

“…MET Eli Lilly [196][197][198] ABT-700 MET AbbVie [199] ARGX111 MET arGEN-x [200] TAK-701 HGF Takeda Pharmaceutical Co [201] …”

Molecularly Targeted Therapies in Non–Small-Cell Lung Cancer Annual Update 2014

“…236, 237 In contrast, LY-2875358 is a bivalent MET receptor antibody that can inhibit both HGF-mediated signaling by binding to the MET receptor, as well as HGF-independent activation of the MET pathway by inducing internalization and degradation of MET. 238 LY-2875358 has confirmed antitumor activity in in vivo and in vitro models. 239, 240 A phase I trial as a single agent and in combination with erlotinib has been reported with no dose limiting toxicities, serious or grade III adverse events.…”

“…238 LY-2875358 has confirmed antitumor activity in in vivo and in vitro models. 239, 240 A phase I trial as a single agent and in combination with erlotinib has been reported with no dose limiting toxicities, serious or grade III adverse events. 241 Currently, LY-2875358 is being evaluated in 2 phase II trials, including a randomized phase II with erlotinib versus erlotinib alone in patients with advanced-stage EGFR-mutated NSCLC (NCT01897480), as well as a single-agent or combined with erlotinib in patients with MET diagnostic positive NSCLC that has progressed on erlotinib.…”

Development of antibody-based c-Met inhibitors for targeted cancer therapy

“…Emibetuzumab (LY-2875358, Eli Lilly) is a humanized, bivalent anti-c-Met antibody that inhibits both ligand-dependent and ligand-independent activation of c-Met. 73 In the case of HGF-dependent c-Met activation, emibetuzumab inhibits HGF binding to c-Met, c-Met phosphorylation, and tumor growth both in vitro and in vivo, similar to a humanized, one-armed 5D5 anti-c-Met antibody (precursor of onartuzumab). In the case of HGF-independent c-Met activation by MET gene amplification in tumors, emibetuzumab promotes internalization and degradation of c-Met.…”