Zolbetuximab as a gastric lineage-directed immunotherapy: mechanistic rationale and translational evidence in CLDN18.2-positive gastroesophageal adenocarcinoma

INTRODUCTION: Zolbetuximab is a first-in-class monoclonal antibody targeting claudin 18.2 (CLDN18.2) demonstrating clinical benefit in gastroesophageal adenocarcinomas. CLDN18.2 is a gastric lineage-restricted tight-junction protein normally concealed in healthy gastric mucosa but aberrantly exposed on tumor cells due to polarity loss following malignant transformation. Unlike canonical oncogenic drivers, CLDN18.2 has no known oncogenic signaling role and serves as a therapeutic anchor rather than a target for tumor growth inhibition. AREAS COVERED: This review synthesizes preclinical, translational, and clinical evidence to clarify zolbetuximab's mechanism of action. Preclinical studies demonstrated that antitumor efficacy is mediated through immune effector pathways - antibody-dependent cellular cytotoxicity (ADCC) via NK cells and complement-dependent cytotoxicity (CDC). The effect requires high antigen density and is enhanced by chemotherapy-induced CLDN18.2 upregulation. Phase I pharmacodynamic studies confirmed that (i) patients retain intact NK and complement function, (ii) ADCC and CDC are rapidly engaged following infusion, and (iii) activity persists across the dosing interval. EXPERT OPINION: Zolbetuximab exemplifies a novel therapeutic class which can be classified as targeted cytolytic antibodies. Future work should test combinations with checkpoint blockade, refine biomarkers, and define resistance mechanisms.