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

• Teresa Burgess

  1Oncology Research, Departments of

• Angela Coxon

  1Oncology Research, Departments of

• Susanne Meyer

  1Oncology Research, Departments of

• Jan Sun

  1Oncology Research, Departments of

• Karen Rex

  1Oncology Research, Departments of

• Trace Tsuruda

  2Protein Sciences,

• Qing Chen

  2Protein Sciences,

• Shu-Yin Ho

  2Protein Sciences,

• Luke Li

  2Protein Sciences,

• Stephen Kaufman

  3Pathology, and

• Kevin McDorman

  3Pathology, and

• Russell C. Cattley

  3Pathology, and

• Jilin Sun

  4Clinical Immunology, Amgen, Inc., Thousand Oaks, California; and

• Gary Elliott

  4Clinical Immunology, Amgen, Inc., Thousand Oaks, California; and

• Ke Zhang

  1Oncology Research, Departments of

• Xiao Feng

  5Abgenix, Inc., Fremont, California

• Xiao-Chi Jia

  5Abgenix, Inc., Fremont, California

• Larry Green

  5Abgenix, Inc., Fremont, California

• Robert Radinsky

  1Oncology Research, Departments of

• Richard Kendall

  1Oncology Research, Departments of

抄録

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)

収録刊行物

• Cancer Research

  Cancer Research 66 (3), 1721-1729, 2006-02-01

  American Association for Cancer Research (AACR)

キーワード

• Cancer Research
• Oncology

詳細情報

• CRID: 1361699995831098368
• NII論文ID: 30018587854
• DOI: 10.1158/0008-5472.can-05-3329
• ISSN: 15387445
• ISSN: 00085472
• Web Site: https://aacrjournals.org/cancerres/article-pdf/66/3/1721/2561867/1721.pdf
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