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Research ArticleDrug Discovery and Translational Medicine

Discovery of Anti–Claudin-1 Antibodies as Candidate Therapeutics against Hepatitis C Virus

Mayo Yamashita, Manami Iida, Minoru Tada, Yoshitaka Shirasago, Masayoshi Fukasawa, Shotaro Nagase, Akihiro Watari, Akiko Ishii-Watabe, Kiyohito Yagi and Masuo Kondoh
Journal of Pharmacology and Experimental Therapeutics April 2015, 353 (1) 112-118; DOI: https://doi.org/10.1124/jpet.114.217653
Mayo Yamashita
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.)
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Manami Iida
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.)
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Minoru Tada
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.)
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Yoshitaka Shirasago
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.)
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Masayoshi Fukasawa
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.)
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Shotaro Nagase
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.)
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Akihiro Watari
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.)
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Akiko Ishii-Watabe
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.)
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Kiyohito Yagi
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.)
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Masuo Kondoh
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.)
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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.

Footnotes

    • Received June 15, 2014.
    • Accepted January 23, 2015.
  • M.Y., M.I., and M.T. contributed equally to this work.

  • This work was supported by a Health and Labor Sciences Research Grant from the Ministry of Health, Labor, and Welfare of Japan; a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan [24390042] (to M.K.); and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan [23590104] (to M.F.); and funds from the Adaptable and Seamless Technology Transfer Program through Target-Driven R&D, Japan Science and Technology Agency [AS242Z01694Q and AS251Z00905Q]; the Takeda Science Foundation; the Nakatomi Foundation; and the Platform for Drug Discovery, Informatics, and Structural Life Science of the Ministry of Education, Culture, Sports, Science, and Technology, Japan; and the Advanced Research for Medical Products Mining Programme of the National Institute of Biomedical Innovation (NIBIO).

  • dx.doi.org/10.1124/jpet.114.217653.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 353 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 353, Issue 1
1 Apr 2015
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Research ArticleDrug Discovery and Translational Medicine

A Claudin-1–Targeted HTA

Mayo Yamashita, Manami Iida, Minoru Tada, Yoshitaka Shirasago, Masayoshi Fukasawa, Shotaro Nagase, Akihiro Watari, Akiko Ishii-Watabe, Kiyohito Yagi and Masuo Kondoh
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 112-118; DOI: https://doi.org/10.1124/jpet.114.217653

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Research ArticleDrug Discovery and Translational Medicine

A Claudin-1–Targeted HTA

Mayo Yamashita, Manami Iida, Minoru Tada, Yoshitaka Shirasago, Masayoshi Fukasawa, Shotaro Nagase, Akihiro Watari, Akiko Ishii-Watabe, Kiyohito Yagi and Masuo Kondoh
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 112-118; DOI: https://doi.org/10.1124/jpet.114.217653
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