title: Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors.
abstract: 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.
authors.affiliation: Department of Oncology Research, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. tburgess@amgen.com
authors.forename: Teresa
authors.initials: T
authors.lastname: Burgess
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Susanne
authors.initials: S
authors.lastname: Meyer
authors.forename: Jan
authors.initials: J
authors.lastname: Sun
authors.forename: Karen
authors.initials: K
authors.lastname: Rex
authors.forename: Trace
authors.initials: T
authors.lastname: Tsuruda
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Shu-Yin
authors.initials: SY
authors.lastname: Ho
authors.forename: Luke
authors.initials: L
authors.lastname: Li
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaufman
authors.forename: Kevin
authors.initials: K
authors.lastname: McDorman
authors.forename: Russell C
authors.initials: RC
authors.lastname: Cattley
authors.forename: Jilin
authors.initials: J
authors.lastname: Sun
authors.forename: Gary
authors.initials: G
authors.lastname: Elliott
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Feng
authors.forename: Xiao-Chi
authors.initials: XC
authors.lastname: Jia
authors.forename: Larry
authors.initials: L
authors.lastname: Green
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
authors.forename: Richard
authors.initials: R
authors.lastname: Kendall
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D007074:Immunoglobulin G; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met