RT Journal Article
SR Electronic
T1 Fully Human Monoclonal Antibodies to Hepatocyte Growth Factor with Therapeutic Potential against Hepatocyte Growth Factor/c-Met–Dependent Human Tumors
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 1721
OP 1729
DO 10.1158/0008-5472.CAN-05-3329
VO 66
IS 3
A1 Burgess, Teresa
A1 Coxon, Angela
A1 Meyer, Susanne
A1 Sun, Jan
A1 Rex, Karen
A1 Tsuruda, Trace
A1 Chen, Qing
A1 Ho, Shu-Yin
A1 Li, Luke
A1 Kaufman, Stephen
A1 McDorman, Kevin
A1 Cattley, Russell C.
A1 Sun, Jilin
A1 Elliott, Gary
A1 Zhang, Ke
A1 Feng, Xiao
A1 Jia, Xiao-Chi
A1 Green, Larry
A1 Radinsky, Robert
A1 Kendall, Richard
YR 2006
UL http://cancerres.aacrjournals.org/content/66/3/1721.abstract
AB 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 β-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 β-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors. (Cancer Res 2006; 66(3): 1721-9) ©2006 American Association for Cancer Research.