Antibody-mediated targeting of Claudins in cancer.

Abstract

Tight junctions (TJs) are large intercellular adhesion complexes that maintain cell polarity in normal epithelia and endothelia. Claudins are critical components of TJs, forming homo- and heteromeric interaction between adjacent cells, which have emerged as key functional modulators of carcinogenesis and metastasis. Numerous epithelial-derived cancers display altered claudin expression patterns, and these aberrantly expressed claudins have been shown to regulate cancer cell proliferation/growth, metabolism, metastasis and cell stemness. Certain claudins can now be used as biomarkers to predict patient prognosis in a variety of solid cancers. Our understanding of the distinct roles played by claudins during the cancer progression has progressed significantly over the last decade and claudins are now being investigated as possible diagnostic markers and therapeutic targets. In this review, we will summarize recent progress in the use of antibody-based or related strategies for targeting claudins in cancer treatment. We first describe pre-clinical studies that have facilitated the development of neutralizing antibodies and antibody-drug-conjugates targeting Claudins (Claudins-1, -3, -4, -6 and 18.2). Next, we summarize clinical trials assessing the efficacy of antibodies targeting Claudin-6 or Claudin-18.2. Finally, emerging strategies for targeting Claudins, including Chimeric Antigen Receptor (CAR)-T cell therapy and Bi-specific T cell engagers (BiTEs), are also discussed.