CLDN18.2 in pancreatic ductal adenocarcinoma: Biomarker assessment, spatial heterogeneity and therapeutic modality selection

Abstract

Claudin 18.2 (CLDN18.2) is expressed in a subset of pancreatic ductal adenocarcinomas (PDACs) and is under clinical development as a target for monoclonal antibodies, antibody‐drug conjugates, immune‐cell engagers, and chimeric antigen receptor (CAR) T‐cell therapies. The testing and clinical‐development pathways established in gastric and gastroesophageal junction cancers provide a useful reference for PDAC; however, PDAC studies have yet to standardize the antibodies, specimen types, scoring methods, or positivity thresholds used for patient selection. Intratumoral and interlesional heterogeneity, discordance between primary and metastatic sites, and changes in membrane localization limit the ability of a single positive or negative sample to capture the tumor's antigenic state. Therapeutic modalities also differ in their requirements for membrane‐antigen coverage, spatial distribution, and the tumor microenvironment. This narrative review draws on peer‐reviewed articles, regulatory documents, ClinicalTrials.gov records, and relevant conference abstracts available through 31 July 2026. This review examines the biological basis, pathological assessment, spatial heterogeneity, and therapeutic development of CLDN18.2 in PDAC, with particular emphasis on treatment selection across different expression states. At baseline, the percentage of tumor cells with 2+/3+ membranous staining is used to describe antigen coverage, H‐score complements this measure by capturing overall expression, and intratumoral and interlesional distribution and specimen representativeness are recorded separately. These findings support the selection of monoclonal antibodies, antibody‐drug conjugates, immune‐cell engagers, and CAR T‐cell therapy according to antigen coverage and spatial distribution, as well as treatment sequencing after disease progression.