Future Landscape of Anti-Claudin 18.2 Antibodies in Gastric AdenocarcinomaCovert, Rogers
Antibodies (Basel) (2025) 14 (1)
Abstract: Advanced gastric adenocarcinoma (GAC) carries a poor prognosis. Targeted therapy in GAC has traditionally been limited to anti-human epidermal growth factor receptor-2 and anti-vascular endothelial growth factor agents. Recent years have brought immune checkpoint therapy to the GAC treatment landscape. However, continued discovery of targeted therapy in GAC is needed. Claudins, transmembrane proteins located in tight junctions of epithelial and endothelial cells, help regulate cellular polarity. Claudin dysregulation has been linked to cancers and other diseases. Claudin 18.2 specifically has become a new novel and exciting biomarker for GAC. Many agents are in the investigative pipeline, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric T-cell therapy. Recently, zolbetuximab, an anti-claudin 18.2 monoclonal antibody, was the first of these agents to get FDA approval. Here, we review zolbetuximab's place in therapy along with other agents being explored.
Advances in Immunotherapy and Targeted Therapy for Gastric Cancer: A Comprehensive ReviewYuan, Bao, Chen
et alBr J Hosp Med (Lond) (2025) 86 (3), 1-24
Abstract: Gastric cancer remains one of the most prevalent and lethal malignancies worldwide, characterized by poor survival rates, particularly in advanced stages. In recent years, a paradigm shift in gastric cancer treatment has been witnessed with the introduction of immunotherapy and targeted therapies. This review provides a detailed examination of current immunotherapeutic strategies, including adoptive cell therapy (ACT), immune checkpoint inhibitors (ICIs), and cancer vaccines. Additionally, it explores advancements in targeted therapies, focusing on the human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor receptor (VEGFR) signaling pathways, as well as emerging targets such as claudin 18.2. Clinical trials investigating chimeric antigen receptor T-cell (CAR-T) therapy, T-cell receptor-engineered T-cell (TCR-T) therapy, and natural killer (NK) cell-based treatments have shown promise, particularly when combined with conventional chemotherapeutic regimens. However, challenges such as cytokine release syndrome, immune-related toxicities, and scalability issues remain significant. The combination of immunotherapy with targeted therapies represents a promising approach to enhance treatment outcomes. Future directions emphasize the need to overcome resistance mechanisms and refine treatment strategies to improve efficacy while reducing adverse effects. This review aims to elucidate the current landscape of immunotherapy and targeted therapy in gastric cancer and to explore their potential in shaping the future of clinical management for this devastating disease.
Claudin 18.2 expression profile in primary tumors and their ovarian metastases: implications for targeted therapyKim, Koo, Kim
et alBMC Cancer (2025) 25 (1), 540
Abstract: Claudin 18.2 (CLDN18.2), a tight junction protein predominantly expressed in the normal gastric epithelium, has recently emerged as a potential therapeutic target in various solid tumors. Despite growing interest, comprehensive data on CLDN18.2 expression across primary tumors from different organs and their corresponding metastatic lesions remain limited.This study analyzed CLDN18.2 expression in 102 patients with primary adenocarcinomas from various organs and their corresponding ovarian metastatic carcinomas and in 81 cases of primary ovarian mucinous tumors using immunohistochemistry. We evaluated the association of CLDN18.2 expression with clinicopathologic features and survival outcomes.The highest CLDN18.2 positivity rate was observed in gastric adenocarcinomas (40%, 12/30), followed by cervical adenocarcinomas (20%, 1/5) and colorectal adenocarcinomas (4%, 2/50). Notably, primary ovarian mucinous tumors showed remarkably high expression rates, reaching 77% overall and 100% in mucinous borderline tumors. In contrast, adenocarcinomas of the appendix and breast lacked CLDN18 expression. While CLDN18.2 expression was generally maintained during metastasis, some variations in expression patterns were observed, particularly in gastric cancers (13%, 4/30). Our analysis found no significant correlation between CLDN18.2 expression and overall survival in the patient cohort.The preserved expression of CLDN18.2 in metastatic tumors underscores its potential utility as a target for therapeutic approaches. Our findings emphasize the importance of evaluating CLDN18.2 status in both primary and metastatic tumors to refine therapeutic strategies.© 2025. The Author(s).
Advances and challenges in gastric cancer testing: the role of biomarkersSun, Puspanathan, Lim
et alCancer Biol Med (2025)
Abstract: Advances in the identification of molecular biomarkers and the development of targeted therapies have enhanced the prognosis of patients with advanced gastric cancer. Several established biomarkers have been widely integrated into routine clinical diagnostics of gastric cancer to guide personalized treatment. Human epidermal growth factor receptor 2 (HER2) was the first molecular biomarker to be used in gastric cancer with trastuzumab being the first approved targeted therapy for HER2-positive gastric cancer. Programmed death-ligand 1 positivity and microsatellite instability can guide the use of immunotherapies, such as pembrolizumab and nivolumab. More recently, zolbetuximab has been approved for patients with claudin 18.2-positive diseases in some countries. More targeted therapies, including savolitinib for MET-positive patients, are currently under clinical investigation. However, the clinical application of these diagnostic approaches could be hampered by many existing challenges, including invasive and costly sampling methods, variability in immunohistochemistry interpretation, high costs and long turnaround times for next-generation sequencing, the absence of standardized and clinically validated diagnostic cut-off values for some biomarkers, and tumor heterogeneity. Novel testing and analysis techniques, such as artificial intelligence-assisted image analysis and multiplex immunohistochemistry, and emerging therapeutic strategies, including combination therapies that integrate immune checkpoint inhibitors with targeted therapies, offer potential solutions to some of these challenges. This article reviews recent progress in gastric cancer testing, outlines current challenges, and explores future directions for biomarker testing and targeted therapy for gastric cancer.Copyright © 2025 The Authors.
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