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: Mayo Yamashita, Manami Iida, Minoru Tada, Yoshitaka Shirasago, Masayoshi Fukasawa, Shotaro Nagase, Akihiro Watari, Akiko Ishii-Watabe, Kiyohito Yagi, Masuo Kondoh
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 353 Issue 1 Pg. 112-8 (Apr 2015) ISSN: 1521-0103 [Electronic] United States
• PMID: 25628391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Antibodies, Monoclonal
• Antiviral Agents
• Claudin-1
• FCGR3A protein, human
• Immunoglobulin Fc Fragments
• Immunoglobulin G
• Receptors, IgG

Topics

• Animals
• Antibodies, Monoclonal (genetics, pharmacology)
• Antiviral Agents (pharmacology)
• Cell Line
• Claudin-1 (immunology)
• Hepacivirus (drug effects)
• Humans
• Immunoglobulin Fc Fragments (genetics)
• Immunoglobulin G (genetics, pharmacology)
• Mice
• Receptors, IgG (metabolism)
• Virus Internalization (drug effects)