A New Anti-c-Met Antibody Selected by a Mechanism-Based Dual-Screening Method: Therapeutic Potential in Cancer

• DOI: 10.1007/s10059-012-0194-z
• Publication Date: 2012-11-23T15:14:42Z
• Authors: Young Mi Oh; Yun-Jeong Song; Saet Byoul Lee; Yunju Jeong; Bogyou Kim; Geun Woong Kim; Kyung Eun Kim; Ji Min Lee; Mi-Young Cho; Jaehyun Choi; Do-Hyun Nam; Paul H Song; Kwang Ho Cheong; Kyung-Ah Kim
• Keywords: Internalization

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