Hepatocyte growth factor (HGF) and its receptor, c-Met, are known to play an important role in tumor growth, metastasis and angiogenesis. Met is widely expressed on various types of tumor cells. Thus, an antagonist molecule that blocks the HGF-Met interaction is expected to have wide therapeutic application in cancer. In the present study, we plan to develop a proprietary soluble Met-Fc adhesin molecule to inhibit HGF-Met interaction. We will (1) construct expression vectors for the extracellular domain of Met fused to human IgG1 Fc, express these adhesin molecules in the mammalian expression system and purify a sufficient quantity of these proteins for in vitro studies; (2) demonstrate the ability of Met-Fc adhesin molecules to inhibit the HGF binding to membrane Met receptors; and (3) demonstrate the ability of Met-Fc to block various in vitro biological activities of HGF including tumor growth promotion, angiogenesis, cell scattering and anti-apoptotic activity. The Phase II study will include scale-up production of the selected proprietary Met-Fc adhesin molecule, in vivo efficacy studies using xenograft nude mouse models with/without chemotherapeutic agents and evaluation of the safety and pharmacokinetics of this molecule in normal animals in preparation for clinical trials in human patients. We expect met-Fc will inhibit tumor growth as well as angiogenesis to provide a novel cancer therapy.
