Soluble c-Met receptors inhibit phosphorylation of c-Met and growth of hepatocyte growth factor: c-Met-dependent tumors in animal models.
c-Met is a receptor tyrosine kinase frequently overexpressed or amplified in many types of human cancers. Hepatocyte growth factor (HGF, also known as scatter factor) is the only known ligand for c-Met. In this study, soluble human and murine c-Met receptor-Fc fusion proteins were generated and were shown to bind to human and murine HGF as measured by fluorescence-activated cell sorting and surface plasmon resonance (Biacore) assays. Also, both human and murine c-Met-Fc showed activity in functional cell assays, inhibiting HGF-induced c-Met phosphorylation in PC3 and 4T1 cells, respectively, and inhibiting HGF-driven cellular invasion in a dose-dependent manner. Pharmacokinetic analysis showed that both reagents were suitable for in vivo testing. Systemic administration of human c-Met-Fc significantly inhibited tumor growth in the human HGF-dependent U-87 MG xenograft model at daily doses of 30 or 100 μg (P < 0.0001). Similarly, murine c-Met-Fc, at 100 μg daily, significantly inhibited tumor growth in the murine HGF-dependent CT-26 syngeneic tumor model (P < 0.002). Human and murine c-Met-Fc seemed to be well-tolerated in animals. In conclusion, both mouse and human versions of c-Met-Fc effectively block HGF-induced activation of c-Met and inhibit growth of tumor xenografts, providing further evidence that c-Met is an important target for oncology therapeutics.
Coxon
Angela
A
Department of Oncology Research, Protein Sciences, and Clinical Immunology, Amgen, Inc, Thousand Oaks, California 91320, USA. acoxon@amgen.com
Rex
Karen
K
Meyer
Susanne
S
Sun
Jianling
J
Sun
Jilin
J
Chen
Qing
Q
Radinsky
Robert
R
Kendall
Richard
R
Burgess
Teresa L
TL
D000818:Animals; D045744:Cell Line, Tumor; D006224:Cricetinae; D005260:Female; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D011993:Recombinant Fusion Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met