A new anti-c-met antibody selected by a mechanism-based dual-screening method: Therapeutic potential in cancer

• Published in: Molecules and cells Vol. 34; no. 6; pp. 523 - 529
• Main Authors: Oh, Y.M., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Song, Y.J., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Lee, S.B., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Jeong, Y.J., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Kim, B.G., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Kim, G.W., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Kim, K.E., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Lee, J.M., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Cho, M.Y., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Choi, J.H., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Nam, D.H., Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea, Song, Paul H, Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Cheong, K.H., Samsung Advanced Institute of Technology, Yongin, Republic of Korea, Kim, K.A., Samsung Advanced Institute of Technology, Yongin, Republic of Korea
• Format: Journal Article
• Language: English
• Published: Springer Korean Society for Molecular and Cellular Biology 01.12.2012; Korea Society for Molecular and Cellular Biology; 한국분자세포생물학회
• Subjects: Akt; anti-c-Met antibody; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; c-Met; cancer therapy; Cell Biology; Cell Line, Tumor; Cell Proliferation; Hepatocyte Growth Factor - antagonists & inhibitors; Hepatocyte Growth Factor - metabolism; HGF; Humans; Isoantibodies - chemistry; Isoantibodies - metabolism; Life Sciences; NEOPLASMAS; NEOPLASME; NEOPLASMS; Neoplasms - drug therapy; Neoplasms - metabolism; Neovascularization, Pathologic; Proto-Oncogene Proteins c-met - metabolism; Xenograft Model Antitumor Assays; 생물학; cancer therapy; anti-c-Met antibody; c-Met; Akt; HGF
• ISSN: 1016-8478; 0219-1032; 0219-1032
• DOI: 10.1007/s10059-012-0194-z

c-Met, the high affinity receptor for hepatocyte growth factor (HGF), is one of the most frequently activated tyrosine kinases in many human cancers and a target for cancer therapy. However, inhibitory targeting of c-Met with antibodies has proven difficult, because most antibodies have intrinsic agonist activity. Therefore, the strategy for reducing the agonism is critical for successful development of cancer therapies based on anti-c-Met antibodies. Here we developed a mechanism-based assay method for rapid screening of anti-c-Met antibodies, involving the determination of Akt phosphorylation and c-Met degradation for agonism and efficacy, respectively. Using the method, we identified an antibody, F46, that binds to human c-Met with high affinity (Kd = 2.56 nM) and specificity, and induces the degradation of c-Met in multiple cancer cells (including MKN45, a gastric cancer cell line) with minimal activation of c-Met signaling. F46 induced c-Met internalization in both HGF-dependent and HGF-independent cells, suggesting that the degradation of c-Met results from antibody-mediated receptor internalization. Furthermore, F46 competed with HGF for binding to c-Met, resulting in the inhibition of both HGF-mediated invasion and angiogenesis. Consistently, F46 inhibited the proliferation of MKN45 cells, in which c-Met is constitutively activated in an HGF-independent manner. Xenograft analysis revealed that F46 markedly inhibits the growth of subcutaneously implanted gastric and lung tumors. These results indicate that F46, identified by a novel mechanism-based assay, induces c-Met degradation with minimal agonism, implicating a potential role of F46 in therapy of human cancers.