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.
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.
Gao
Chong-Feng
CF
Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick, Northeast, Grand Rapids, MI 49503, USA.
Xie
Qian
Q
Zhang
Yu-Wen
YW
Su
Yanli
Y
Zhao
Ping
P
Cao
Brian
B
Furge
Kyle
K
Sun
Jan
J
Rex
Karen
K
Osgood
Tao
T
Coxon
Angela
A
Burgess
Teresa L
TL
Vande Woude
George F
GF
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use*; D019898:Autocrine Communication / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005341:Fibrinolysin / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000276:immunology*; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D057134:Antibodies, Neutralizing; D008024:Ligands; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator