Development and anti‐tumor activities of claudin‐4‐specific monoclonal antibodies (1062.8)

Abstract

Claudin (CLDN) is a key component of the epithelial tight junction. Expression of the various CLDNs differs among tissues and is deregulated in malignant tumors. For example, CLDN4 is frequently overexpressed in pancreatic, breast, and ovarian cancers and therefore may be an attractive target for anticancer drugs. However, the low antigenicity of CLDN4 has hampered the development of antibody‐based CLDN4‐targeted cancer therapy. We successfully generated monoclonal antibodies (mAbs) to CLDN4 and evaluated their anti‐tumor activity. Briefly, we immunized rats with plasmids containing the CLDN4 coding sequence. We fused the resulting B cells with myeloma cells and screened 8 hybridoma clones that produced anti‐CLDN4 mAbs. All 8 mAbs bound to CLDN4‐expressing cells but not to those expressing CLDN1, 2, 5, 6, 7or 9. All 8 mAbs showed CLDN4 binding‐dependent activation of the Fcγ receptor. A clone with high affinity to CLDN4 suppressed tumor growth in vitro and in vivo. Interestingly, treatment of cancer cells with the clone of CLDN4‐specific mAb and an anti‐cancer drug (5‐flurouracil or cisplatin) had a synergistic cytotoxic effect. Specifically, mAb treatment increased intracellular drug levels. Our findings indicate that CLDN4 mAbs are promising tools for CLDN4‐targeted cancer therapy.Grant Funding Source: supported by the Ministry of Health, Labor, and Welfare of Japan