Claudin-18 (CLDN18), a member of the claudin family of tight junction proteins, plays a critical role in maintaining epithelial barrier integrity and regulating paracellular permeability. It exists as two major splice variants: CLDN18.1. primarily expressed in the lung, and CLDN18.2. which is selectively expressed in gastric mucosa. Unlike CLDN18.1. CLDN18.2 exhibits restricted expression in normal tissues but becomes aberrantly exposed in various cancers, including gastric, esophageal, and pancreatic adenocarcinomas, due to disrupted cell polarity during malignant transformation. This unique expression pattern makes CLDN18.2 a promising therapeutic target, particularly for cancers with limited treatment options.
CLDN18-targeted antibodies, such as monoclonal antibodies (mAbs) and bispecific antibodies, are designed to exploit this tumor-specific antigen. Zolbetuximab, a first-in-class anti-CLDN18.2 mAb, has shown clinical efficacy in HER2-negative, CLDN18.2-positive gastric cancers by inducing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Recent phase III trials highlight its potential to improve survival when combined with chemotherapy. Additionally, bispecific antibodies engaging T cells (e.g., CLDN18.2xCD3) or dual-targeting strategies (e.g., CLDN18.2xPD-L1) are under investigation to enhance antitumor activity and overcome resistance.
Despite progress, challenges like heterogeneous CLDN18.2 expression and on-target/off-tumor toxicity in CLDN18.1-expressing tissues require further optimization. Ongoing research focuses on biomarker-driven patient stratification and novel antibody engineering to maximize therapeutic benefits.