Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors.
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 beta-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 beta-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors.
Burgess
Teresa
T
Department of Oncology Research, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. tburgess@amgen.com
Coxon
Angela
A
Meyer
Susanne
S
Sun
Jan
J
Rex
Karen
K
Tsuruda
Trace
T
Chen
Qing
Q
Ho
Shu-Yin
SY
Li
Luke
L
Kaufman
Stephen
S
McDorman
Kevin
K
Cattley
Russell C
RC
Sun
Jilin
J
Elliott
Gary
G
Zhang
Ke
K
Feng
Xiao
X
Jia
Xiao-Chi
XC
Green
Larry
L
Radinsky
Robert
R
Kendall
Richard
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D005260:Female; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007074:Immunoglobulin G; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met