CLDN18.2-Targeted Therapy in Gastrointestinal Cancers
Andrea Dominguez Wiscovitch1, Ricardo J Sanchez Mendez2, Jennifer Chuy3
1Department of Medicine, NYU Langone Health, New York, NY 10016, USA.
Cancers
|December 11, 2025
Summary
Claudin-18.2 (CLDN18.2) is a promising target for gastrointestinal cancers. This review explores CLDN18.2 therapies beyond zolbetuximab, including novel agents and combinations, to improve patient outcomes.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- Gastrointestinal cancers (gastric, pancreatic, biliary) have poor prognoses due to late detection and limited treatments.
- Claudin-18.2 (CLDN18.2), a gastric epithelium protein aberrantly expressed in GI tumors, is a key therapeutic target.
- Zolbetuximab, a CLDN18.2-targeting antibody, marks a significant advancement.
Purpose of the Study:
- To provide a comprehensive review of CLDN18.2-directed therapies across gastrointestinal malignancies.
- To analyze emerging treatment modalities, including bispecific antibodies, ADCs, and CAR T-cell therapies.
- To discuss combination strategies, biomarker challenges, resistance mechanisms, and future research directions.
Main Methods:
- Narrative review of CLDN18.2-targeted therapies in gastrointestinal cancers.
- Analysis of zolbetuximab's impact and evaluation of novel therapeutic platforms.
- Examination of CLDN18.2/PD-L1 co-expression, combination rationale, and resistance mechanisms.
Main Results:
- CLDN18.2-targeted therapies show promise across gastric, pancreatic, and biliary cancers.
- Emerging modalities like bispecific antibodies and ADCs offer diverse mechanisms and efficacy profiles.
- Combination strategies with immune checkpoint inhibitors are being explored, alongside challenges in biomarker testing and resistance.
Conclusions:
- CLDN18.2-targeted therapies represent a rapidly evolving field with significant potential for improving outcomes in gastrointestinal cancers.
- Addressing tumor heterogeneity, resistance, and standardizing biomarker testing are crucial for optimizing treatment integration.
- Further research into novel agents, combination therapies, and overcoming resistance mechanisms is warranted to fully realize the therapeutic potential of CLDN18.2.
Keywords:
biliary tract cancerclaudin18.2gastric cancergastroesophageal junction adenocarcinomapancreatic cancerMore Related Videos
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