The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies (hMAbs) that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation. Anti-c-Met hMAbs that bind the c-Met ECD were produced using Abgenix’s XenoMouse® mice immunized with a recombinant c-Met ECD-Fc fusion protein or NIH 3T3 cells engineered to overexpress human c-Met. We identified antibodies representing four independent epitope classes that inhibited both ligand binding and ligand-dependent activation of c-Met in A549 cells. In addition, these antibodies inhibited ligand-dependent growth in soft agar and tubular morphogenesis. The antibodies antagonized c-Met function by blocking ligand-dependent receptor activation and by subsequently inducing internalization and downregulation of the receptor. The antibodies with the greatest potency in the biochemical and functional assays were characterized further in vivo. Significant inhibition of c-Met activity (>80% lasting for 72-96 hrs) in excised tumors corresponded to tumor growth inhibition in multiple xenograft tumor models. Several of the antibodies identified potently inhibited the growth of tumors engineered to overexpress human HGF and human c-Met (S114 NIH 3T3) when grown subcutaneously in athymic mice. Furthermore, the anti bodies inhibited the growth of xenograft U87 MG human glioblastoma, A549 lung carcinoma, and GTL16 gastric cancer tumors by 50-98%. The findings demonstrate that targeting c-Met with human monoclonal antibodies is a promising novel therapeutic approach for the treatment of cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]