title: A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer.
abstract: The bispecific antibody is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a bispecific antibody (BsAb) that can bind cellular-mesenchymal to epithelial transition factor (c-MET, overexpressed in several human solid tumor), and programmed death-1 (PD-1, involved in cancer cell immune evasion) with high affinity and specificity. We found that BsAb can induce the degradation of c-MET protein in cancer cells, including MKN45, a gastric cancer cell line, and A549, a lung cancer cell line. BsAb inhibited hepatocyte growth factor (HGF)-mediated proliferation, migration, and antiapoptosis, and downregulated HGF-stimulated phosphorylation of c-MET, protein kinase B (AKT), and extracellular signal-regulated kinase (ERK1/2). BsAb can also rescue T cell activation. Furthermore, xenograft analysis revealed that BsAb markedly inhibits the growth of subcutaneously implanted tumors and chronic inflammation. On the basis of these results, we have identified a potential bispecific drug, which can effectively target c-MET and PD-1 for the treatment of human solid cancers.
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai, China.
authors.forename: Zu-Jun
authors.initials: ZJ
authors.lastname: Sun
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai, China.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Hou
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai, China.
authors.forename: Yu-Xiong
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai, China.
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Yuan
authors.affiliation: Department of Medical Oncology, Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Hui-Jie
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000074322:Antineoplastic Agents, Immunological; C066855:HGF protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: cellular-mesenchymal to epithelial transition factor; programmed death-1