title: A new anti-c-Met antibody selected by a mechanism-based dual-screening method: therapeutic potential in cancer.
abstract: 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.
authors.affiliation: Therapeutic Antibody Group, Samsung Advanced Institute of Technology, Yongin 446-712, Korea.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Oh
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Song
authors.forename: Saet Byoul
authors.initials: SB
authors.lastname: Lee
authors.forename: Yunju
authors.initials: Y
authors.lastname: Jeong
authors.forename: Bogyou
authors.initials: B
authors.lastname: Kim
authors.forename: Geun Woong
authors.initials: GW
authors.lastname: Kim
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Kim
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Cho
authors.forename: Jaehyun
authors.initials: J
authors.lastname: Choi
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.forename: Paul H
authors.initials: PH
authors.lastname: Song
authors.forename: Kwang Ho
authors.initials: KH
authors.lastname: Cheong
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Kim
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007518:Isoantibodies / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D007518:Isoantibodies; C051138:anti-c antibody; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met