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 Fcγ IIIa 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.