Presentation Abstract

Abstract Number: 695
Presentation Title: LA480, a c-Met antibody with neutralization and internalization properties, inhibits HGF-dependent and HGF-independent c-Met pathway activation and tumor growth
Presentation Time: Sunday, Apr 18, 2010, 2:00 PM - 5:00 PM
Location: Exhibit Hall A-C, Poster Section 26
Poster Section: 26
Poster Board Number: 2
Author Block: Mark A. Wortinger1, Wei Zeng1, Wei Jennifer Yang1, Victoria Peek1, Lei Yan1, Jirong Lu1, Chi-Kin Chow1, Peter Vaillancourt2, Julian Davies2, Irene Denning2, Spring Weir1, James Wooldridge1, Ling Liu1. 1Eli Lilly and Co, Indianapolis, IN; 2Applied Molecular Evolution, Lilly Biotechnology Center, San Diego, CA
Abstract Body: c-Met is a receptor tyrosine kinase that binds hepatocyte growth factor (HGF) and has been implicated in human cancer. Inappropriate activation of c-Met can be induced by ligand-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation, or by ligand-dependent autocrine or paracrine mechanisms. Indeed, amplification of the c-Met gene, with consequent protein overexpression and constitutive kinase activation, has been reported in a number of human cancers, including gastric, esophageal and non-small-cell lung carcinomas. Activating mutations of the c-Met gene have been found in a subset of patients with hereditary and sporadic papillary renal cancer, lung cancer, childhood hepatocellular carcinoma and gastric carcinoma. Another common constitutive c-Met activation in human tumors is increased protein expression as a consequence of transcriptional upregulation, in the absence of gene amplification. c-Met expression level has been correlated with poor prognosis in multiple tumor types. In addition, cMet activation by an elevated level of HGF has also been described in gliobastoma, breast carcinomas, rhabdomyosarcoma and osteosarcoma. We report here that LA480, a humanized monoclonal c-Met antibody, inhibits HGF-dependent and HGF-independent c-Met pathway activation and tumor growth. Our data demonstrate that LA480 blocks binding of HGF to c-Met as shown by ELISA, blocks HGF stimulation of phospho-Met in HCT116 cells, and blocks HGF stimulation of primary human hepatocyte proliferation. Moreover, LA480 internalizes and depletes cell surface c-Met, significantly reduces phospho-c-Met and total c-Met in multiple tumor cell lines, and inhibits proliferation of tumor cell lines that have c-Met gene amplification. In addition, LA480 does not stimulate biological activities that are elicited by HGF. Furthermore, LA480 reduces total c-Met and phospho-Met in xenograft tumors and significantly inhibits tumor growth in both ligand-independent and ligand-dependent mouse xenograft models. These findings suggest that LA480 may be a promising therapy for treatment of cancers driven by ligand-dependent and ligand-independent c-Met activation.