RT Journal Article
SR Electronic
T1 Discovery of anti-claudin-1 antibodies as candidate therapeutics against hepatitis C virus
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.114.217653
DO 10.1124/jpet.114.217653
A1 Mayo Yamashita
A1 Manami Iida
A1 Minoru Tada
A1 Yoshitaka Shirasago
A1 Masayoshi Fukasawa
A1 Shorato Nagase
A1 Akihiro Watari
A1 Akiko Ishii-Watabe
A1 Kiyohito Yagi
A1 Masuo Kondoh
YR 2015
UL http://jpet.aspetjournals.org/content/early/2015/01/27/jpet.114.217653.abstract
AB 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 4 clones of mouse anti-CLDN1 monoclonal antibody (mAb) that prevented HCV infection in vitro. Two of these mAbs showed the highest anti-viral 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 IgG4 form of human chimeric anti-CLDN1 mAb may be a candidate molecule for clinically applicable HCV therapy.