title: Anti-cancer Activity of Novel TM4SF5-Targeting Antibodies through TM4SF5 Neutralization and Immune Cell-Mediated Cytotoxicity.
abstract: The transmembrane four L6 family member 5 (TM4SF5) protein is a novel molecular target for the prevention and treatment of hepatocellular carcinoma. TM4SF5 is highly expressed in liver, colon, esophageal, and pancreatic cancers and is implicated in tumor progression. Here, we screened monoclonal antibodies that specifically bound to the extracellular loop 2 (EC2) of TM4SF5 from a phage-displayed murine antibody (single-chain variable fragment; scFv) library. We constructed and characterized chimeric antibodies, Ab27 and Ab79, of scFv fused with Fc domain of human IgG1. The affinity (KD) of Ab27 and Ab79 for soluble EC2 was approximately 9.2 nM and 16.9 nM, respectively, as determined by surface plasmon resonance analysis. Ab27 and Ab79 efficiently bound to native TM4SF5 on the cell surface were internalized into the cancer cells, leading to a decrease in cell surface TM4SF5. Ab27 and Ab79 inhibited the proliferation and invasion of TM4SF5-positive liver and colon cancer cells and reduced FAK and c-Src phosphorylation. Ab27 and Ab79 also enhanced anoikis sensitivity and reduced survivin. Ab27 mediated antibody-dependent cell-mediated cytotoxicityin vitro. Ab27 and Ab79 efficiently inhibited tumor growth in a liver cancer xenograft model. These results strongly support the further development of Ab27 as a novel anti-cancer agent in the clinic.
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Ahn
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Biochemicals & Synthetic Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea.
authors.forename: Jin Myeong
authors.initials: JM
authors.lastname: Song
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea.
authors.forename: Yunhee
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea;; Department of Functional Genomics, Korea University of Science and Technology, Daejon, Korea.
authors.forename: Dongjoon
authors.initials: D
authors.lastname: Ko
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea.
authors.forename: Inpyo
authors.initials: I
authors.lastname: Choi
authors.affiliation: Biochemicals & Synthetic Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea.
authors.forename: Sang Jick
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea;; Department of Functional Genomics, Korea University of Science and Technology, Daejon, Korea.
authors.forename: Semi
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008565:Membrane Proteins; C111029:TM4SF5 protein, human
keywords: TM4SF5; antibody; colon cancer; liver cancer; phage display.; therapeutics