title: Efficacy and safety evaluation of claudin-4-targeted antitumor therapy using a human and mouse cross-reactive monoclonal antibody.
abstract: Claudin-4 (CLDN-4), a tight-junction protein, is overexpressed in various malignant tumors, including gastric, colorectal, pancreatic, and breast cancers. However, CLDN-4 is also expressed in normal tissues, including the liver, pancreas, kidney, and small intestine. Whether CLDN-4 is an effective and safe target for cancer therapy has been unclear owing to the lack of a binder with both CLDN-4 specificity and cross-reactivity to human and murine cells. In this study, we successfully generated a rat anti-CLDN-4 monoclonal antibody (5D12) that was specific to, and cross-reactive with, human and mouse CLDN-4. 5D12 recognized the second extracellular domain of human CLDN-4 in a conformation-dependent manner. A human-rat chimeric IgG1 of 5D12 (xi-5D12) activated the FcγIIIa receptor, indicating the activation of antibody-dependent cellular cytotoxicity in CLDN-4-expressing cells. Moreover, xi-5D12 significantly suppressed tumor growth in mice bearing human colorectal and gastric tumors without apparent adverse effects, such as weight loss or liver and kidney damage. These results suggest that CLDN-4 is a potent target for cancer therapy and that an anti-CLDN-4 antibody is a promising candidate anticancer agent.
authors.affiliation: Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kawahigashi
authors.affiliation: Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hata
authors.affiliation: Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan.
authors.forename: Xiangru
authors.initials: X
authors.lastname: Li
authors.affiliation: Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Watari
authors.affiliation: Division of Biological Chemistry and Biologicals National Institute of Health Sciences Tokyo 158-0098 Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tada
authors.affiliation: Division of Biological Chemistry and Biologicals National Institute of Health Sciences Tokyo 158-0098 Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishii-Watabe
authors.affiliation: Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Biochemistry and Cell Biology National Institute of Infectious Diseases Tokyo 162-8640 Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Fukasawa
authors.affiliation: Department of Molecular Pathology Nara Medical University Nara 634-8521 Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kuniyasu
authors.affiliation: Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan.
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Yagi
authors.affiliation: Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan.
authors.forename: Masuo
authors.initials: M
authors.lastname: Kondoh
keywords: Cancer therapy; claudin; efficacy; monoclonal antibody; safety