Potency of Claudin-targeting as Antitumor Therapy

Approximately 90% of malignant tumors are derived from the epithelium. Epithelium has well-developed tight junctions (TJs), which become deregulated and disrupted during epithelial transformation. Claudin-4, a pivotal functional and structural component of TJs, is often overexpressed in human cancers. In the present study, we prepared a claudin-4 binder, the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE), fused to a cytotoxic molecule (C-CPE-PSIF) and found that C-CPE-PSIF is toxic to claudin-4-expressing cells. Interestingly, C-CPE-PSIF was less toxic in polarized than depolarized cells, and treatment of polarized cells with C-CPE-PSIF from the basal but not apical side was cytotoxic. C-CPE-PSIF also exhibits antitumor activity. C-CPE mutants with alanine substitutions were more cytotoxic than C-CPE. These findings indicate that the claudin-4 binder, C-CPE, is a potent lead molecule for the development of claudin-targeted tumor therapy.