Generation and characterization of a human-mouse chimeric antibody against the extracellular domain of claudin-1 for cancer therapy using a mouse model.
Claudin-1 (CLDN-1), an integral transmembrane protein, is an attractive target for drug absorption, prevention of infection, and cancer therapy. Previously, we generated mouse anti-CLDN-1 monoclonal antibodies (mAbs) and found that they enhanced epidermal absorption of a drug and prevented hepatitis C virus infection in human hepatocytes. Here, we investigated anti-tumor activity of a human-mouse chimeric IgG1, xi-3A2, from one of the anti-CLDN-1 mAbs, clone 3A2. Xi-3A2 accumulated in the tumor tissues in mice bearing with human CLDN-1-expressing tumor cells. Xi-3A2 activated Fcγ receptor IIIa-expressing reporter cells in the presence of human CLDN-1-expressing cells, suggesting xi-3A2 has a potential to exhibit antibody-dependent cellular cytotoxicity against CLDN-1 expressing tumor cells. We also constructed a mutant xi-3A2 antibody with Gly, Ser, and Ile substituted with Ala, Asp, and Arg at positions 236, 239, and 332 of the Fc domain. This mutant antibody showed greater activation of Fcγ receptor IIIa and in vivo anti-tumor activity in mice bearing human CLDN-1-expressing tumors than xi-3A2 did. These findings indicate that the G236A/S239D/I332E mutant of xi-3A2 might be a promising lead for tumor therapy.
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Yosuke
Y
Hashimoto
Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Tokyo 158-0098, Japan.
Minoru
M
Tada
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Manami
M
Iida
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Shotaro
S
Nagase
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Tomoyuki
T
Hata
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Akihiro
A
Watari
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Yoshiaki
Y
Okada
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Takefumi
T
Doi
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Masayoshi
M
Fukasawa
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Kiyohito
K
Yagi
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan. Electronic address: masuo@phs.osaka-u.ac.jp.
Masuo
M
Kondoh
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D045744:Cell Line, Tumor; D002678:Chimera; D062445:Claudin-1 / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D062445:Claudin-1
Anti-cancer agent; Chimeric antibody; Claudin-1; Fcγ receptor IIIa