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[Cancer Research 66, 1721-1729, February 1, 2006]
© 2006 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Fully Human Monoclonal Antibodies to Hepatocyte Growth Factor with Therapeutic Potential against Hepatocyte Growth Factor/c-Met–Dependent Human Tumors

Teresa Burgess1, Angela Coxon1, Susanne Meyer1, Jan Sun1, Karen Rex1, Trace Tsuruda2, Qing Chen2, Shu-Yin Ho2, Luke Li2, Stephen Kaufman3, Kevin McDorman3, Russell C. Cattley3, Jilin Sun4, Gary Elliott4, Ke Zhang1, Xiao Feng5, Xiao-Chi Jia5, Larry Green5, Robert Radinsky1 and Richard Kendall1

Departments of 1 Oncology Research, 2 Protein Sciences, 3 Pathology, and 4 Clinical Immunology, Amgen, Inc., Thousand Oaks, California; and 5 Abgenix, Inc., Fremont, California

Requests for reprints: Teresa Burgess, Amgen, Inc., Oncology Research, M/S 5-2-A, One Amgen Center Drive, Thousand Oaks, CA 91320-1799. Phone: 805-447-2493; Fax: 805-375-8368; E-mail: tburgess{at}amgen.com.

c-Met is a well-characterized receptor tyrosine kinase for hepatocyte growth factor (HGF). Compelling evidence from studies in human tumors and both cellular and animal tumor models indicates that signaling through the HGF/c-Met pathway mediates a plethora of normal cellular activities, including proliferation, survival, migration, and invasion, that are at the root of cancer cell dysregulation, tumorigenesis, and tumor metastasis. Inhibiting HGF-mediated signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of human tumors. Toward this goal, we generated and characterized five different fully human monoclonal antibodies that bound to and neutralized human HGF. Antibodies with subnanomolar affinities for HGF blocked binding of human HGF to c-Met and inhibited HGF-mediated c-Met phosphorylation, cell proliferation, survival, and invasion. Using a series of human-mouse chimeric HGF proteins, we showed that the neutralizing antibodies bind to a unique epitope in the ß-chain of human HGF. Importantly, these antibodies inhibited HGF-dependent autocrine-driven tumor growth and caused significant regression of established U-87 MG tumor xenografts. Treatment with anti-HGF antibody rapidly inhibited tumor cell proliferation and significantly increased the proportion of apoptotic U-87 MG tumor cells in vivo. These results suggest that an antibody to an epitope in the ß-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors. (Cancer Res 2006; 66(3): 1721-9)




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