Claudin 1, 4, 6 and 18 isoform 2 as targets for the treatment of cancer (Review).

The 24 claudin (CLDN) genes in the human genome encode 26 representative CLDN family proteins. CLDNs are tetraspan‑transmembrane proteins at tight junctions. Because several CLDN isoforms, such as CLDN6 and CLDN18.2, are specifically upregulated in human cancer, CLDN‑targeting monoclonal antibodies (mAbs), antibody‑drug conjugates (ADCs), bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells have been developed. In the present review, CLDN1‑, 4‑, 6‑ and 18.2‑targeting investigational drugs in clinical trials are discussed. CLDN18.2‑directed therapy for patients with gastric and other types of cancer is the most advanced area in this field. The mouse/human chimeric anti‑CLDN18.2 mAb zolbetuximab has a single‑agent objective response rate (ORR) of 9%, and increases progression‑free and overall survival in combination with chemotherapy. The human/humanized anti‑CLDN18.2 mAb osemitamab, and ADCs AZD0901, IBI343 and LM‑302, with single‑agent ORRs of 28‑60%, have been tested in phase III clinical trials. In addition, bsAbs, CAR T cells and their derivatives targeting CLDN4, 6 or 18.2 are in phase I and/or II clinical trials. AZD0901, IBI343, zolbetuximab and the anti‑CLDN1 mAb ALE.C04 have been granted fast track designation or priority review designation by the US Food and Drug Administration.