Abstract B233: c-Met antagonist Avimer™ polypeptide that exhibits potent in vivo and in vitro inhibitor activity

Abstract

Abstract c-Met is a receptor tyrosine kinase (RTK) that is activated upon binding to its only known ligand, hepatocyte growth factor (HGF). Although essential in development, aberrant c-Met signaling can lead to oncogenesis by promoting proliferation, survival, metastasis, and angiogenesis. Deregulated expression/activation of cMet is found in many neoplasms, and the linkage to disease severity and poor prognosis make this RTK an attractive candidate for targeted anticancer therapy. Challenges of inhibiting c-Met/HGF signaling with a classic antibody therapeutic approach have included: (1) the inhibition of receptor activation required more than one antibody, and (2) bivalent antibodies caused receptor activation. Using a novel non-antibody protein technology platform, we have identified potent polypeptide inhibitors of HGF-mediated c-Met activation. This non-antibody class of proteins, termed Avimer (avidity multimer) polypeptides, are based on naturally occurring domain (e.g., A-domain) containing proteins and can be generated using a phage display library and expressed in E. coli. c-Met antagonist Avimer polypeptides potently inhibit HGF-mediated receptor activation, migration, and proliferation in in vitro assays. Improvement in pharmacokinetic profile gained through attaching polyethylene glycol molecules to avimers enabled in vivo studies. In multiple preclinical tumor models (U87MG glioblastoma, KP-4 pancreatic, U118 glioblastoma), Avimer-treated animals exhibited reduced cMet activation in xenografts and significantly decreased tumor growth. These data indicate that the c-Met antagonist Avimer polypeptides are potent c-Met inhibitors and offer an alternative to small molecules or antibodies in targeting cMet/HGF pathway for anticancer therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B233.