title: Discovery of anti-claudin-1 antibodies as candidate therapeutics against hepatitis C virus.
abstract: Claudin-1 (CLDN1), a known host factor for hepatitis C virus (HCV) entry and cell-to-cell transmission, is a target molecule for inhibiting HCV infection. We previously developed four clones of mouse anti-CLDN1 monoclonal antibody (mAb) that prevented HCV infection in vitro. Two of these mAbs showed the highest antiviral activity. Here, we optimized the anti-CLDN1 mAbs as candidates for therapeutics by protein engineering. Although Fab fragments of the mAbs prevented in vitro HCV infection, their inhibitory effects were much weaker than those of the whole mAbs. In contrast, human chimeric IgG1 mAbs generated by grafting the variable domains of the mouse mAb light and heavy chains inhibited in vitro HCV infection as efficiently as the parental mouse mAbs. However, the chimeric IgG1 mAbs activated Fcγ receptor, suggesting that cytotoxicity against mAb-bound CLDN1-expressing cells occurred through the induction of antibody-dependent cellular cytotoxicity (ADCC). To avoid ADCC-induced side effects, we prepared human chimeric IgG4 mAbs. The chimeric IgG4 mAbs did not activate Fcγ receptor or induce ADCC, but they prevented in vitro HCV infection as efficiently as did the parental mouse mAbs. These findings indicate that the IgG4 form of human chimeric anti-CLDN1 mAb may be a candidate molecule for clinically applicable HCV therapy.
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.).
authors: Mayo
authors: M
authors: Yamashita
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.).
authors: Manami
authors: M
authors: Iida
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.).
authors: Minoru
authors: M
authors: Tada
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.).
authors: Yoshitaka
authors: Y
authors: Shirasago
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.) masuo@phs.osaka-u.ac.jp fuka@nih.go.jp.
authors: Masayoshi
authors: M
authors: Fukasawa
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.).
authors: Shotaro
authors: S
authors: Nagase
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.).
authors: Akihiro
authors: A
authors: Watari
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.).
authors: Akiko
authors: A
authors: Ishii-Watabe
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.).
authors: Kiyohito
authors: K
authors: Yagi
authors: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (M.Y., M.I., S.N., A.W., K.Y., M.K.); Division of Biological Chemistry and Biologicals, National Institutes of Health Sciences, Tokyo, Japan (M.T., A.I.-W.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan (Y.S., M.F.); and Graduate School of Biological Science, Tokyo University of Science, Chiba, Japan (Y.S.) masuo@phs.osaka-u.ac.jp fuka@nih.go.jp.
authors: Masuo
authors: M
authors: Kondoh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D062445:Claudin-1 / Q000276:immunology*; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D017452:Receptors, IgG / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D062445:Claudin-1; C496124:FCGR3A protein, human; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D017452:Receptors, IgG