Research advances in targeting claudin 18.2 in pancreatic ductal adenocarcinoma treatment

Abstract

Claudin 18.2 (CLDN18.2) is a tight junction protein expressed only by gastric mucosal epithelial cells with known functions involving the regulation of cell barriers, polarity, and ion permeability. Research in cancers of the digestive system has shown that CLDN18.2 is often ectopically activated and highly expressed in gastric/gastroesophageal junction adenocarcinoma, and pancreatic cancer, identifying CLDN18.2 as a potential therapeutic target. Immunotherapy strategies targeting CLDN18.2 include monoclonal antibodies, chimeric antigen receptor T cells, diclonal antibodies, and antibody conjugates, and such therapies have shown promising efficacy in gastric cancer. Zolbetuximab, a monoclonal antibody, has also shown promise in the treatment of pancreatic ductal adenocarcinoma (PDAC). This review summarizes and discusses major advances related to the function and targeting of CLDN18.2 in PDAC. By understanding the structure, function, and expression of CLDN18.2 in PDAC as well as the efficacy and mechanisms of treatment methods related to CLDN18.2, we hope to provide insights for the future development of treatment strategies for CLDN18.2-positive PDAC. However, current evidence on the clinical efficacy of targeting CLDN18.2 in PDAC remains preliminary and fragmented, derived mostly from small studies or gastric cancer extrapolation. Much more research is needed before clinical application of CLDN18.2-directed strategies.

Keywords: Claudin 18.2; Pancreatic ductal adenocarcinoma; Targeted therapy; Research progress; Treatment

Core Tip: Claudin 18.2 (CLDN18.2) is expressed in pancreatic ductal adenocarcinoma (PDAC) and represents a promising therapeutic target. This review summarizes current evidence on CLDN18.2-directed therapies, including monoclonal antibodies, antibody drug conjugates, chimeric antigen receptor-T cells, bispecific antibodies, and other emerging strategies. We also outline unique challenges specific to CLDN18.2-positive PDAC, such as an abundance of cancer-associated fibroblasts, a profoundly immunosuppressive microenvironment, and intratumoral antigen heterogeneity. At present, this field remains in its preliminary stage, with most available data derived from small-scale clinical studies or extrapolated from gastric cancer research. Further PDAC-tailored preclinical and clinical investigations are urgently needed.