Discovery of anti-Claudin-1 antibodies as candidate therapeutics against hepatitis C virus

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Abstract

Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. 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 Fcg receptor, suggesting that cytotoxicity against mAb-bound CLDN1- expressing cells occurred through the induction of antibodydependent cellular cytotoxicity (ADCC). To avoid ADCC-induced side effects, we prepared human chimeric IgG4 mAbs. The chimeric IgG4 mAbs did not activate Fcg 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 mAbmay be a candidate molecule for clinically applicable HCV therapy.

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Yamashita, M., Iida, M., Tada, M., Shirasago, Y., Fukasawa, M., Nagase, S., … Kondoh, M. (2015). Discovery of anti-Claudin-1 antibodies as candidate therapeutics against hepatitis C virus. Journal of Pharmacology and Experimental Therapeutics, 353(1), 112–118. https://doi.org/10.1124/jpet.114.217653

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