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Therapeutic potential of hepatocyte growth factor/scatter factor neutralizing antibodies: Inhibition of tumor growth in both autocrine and paracrine hepatocyte growth factor/scatter factor:c-Met-driven models of leiomyosarcoma

2009; American Association for Cancer Research; Volume: 8; Issue: 10 Linguagem: Inglês

10.1158/1535-7163.mct-09-0125

1538-8514

Chong Gao, Qian Xie, Yuwen Zhang, Yanli Su, Ping Zhao, Brian Cao, Kyle Furge, Jan Sun, Karen Rex, Tao Osgood, Angela Coxon, Teresa L. Burgess, George F. Vande Woude,

Pancreatic function and diabetes

Abstract Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, have been implicated in the growth and progression of a variety of solid human tumors. Thus, inhibiting HGF/SF:c-Met signaling may provide a novel therapeutic approach for treating human tumors. We have generated and characterized fully human monoclonal antibodies that bind to and neutralize human HGF/SF. In this study, we tested the effects of the investigational, human anti-human HGF/SF monoclonal antibody, AMG 102, and a mixture of mouse anti-human HGF/SF monoclonal antibodies (Amix) on HGF/SF-mediated cell migration, proliferation, and invasion in vitro. Both agents had high HGF/SF-neutralizing activity in these cell-based assays. The HGF/SF:c-Met pathway has been implicated in the growth of sarcomas; thus, we also investigated the effect of AMG 102 on the growth of human leiomyosarcoma (SK-LMS-1) in HGF/SF transgenic C3H severe combined immunodeficient mice engineered to express high levels of human HGF/SF, as well as tumor growth of an autocrine variant of the SK-LMS-1 cell line (SK-LMS-1TO) in nude mice. The results indicate that interrupting autocrine and/or paracrine HGF/SF:c-Met signaling with AMG 102 has profound antitumor effects. These findings suggest that blocking HGF/SF:c-Met signaling may provide a potent intervention strategy to treat patients with HGF/SF:c-Met–dependent tumors. [Mol Cancer Ther 2009;8(10):2803–10]