Claudin Proteins in Cancer Development

Targeting Claudin18.2 for cancer theranostics: From molecular imaging to precision therapy Claudin18.2 as a cancer therapeutic target CLDN18.2 has emerged as a promising therapeutic target in digestive system cancers, drawing growing interest in the field of precision oncology. Current investigational CLDN18.2-targeted agents include monoclonal antibodies (mAbs), bispecific antibodies (BsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cell therapies (Figure 2). This section provides an overview of the key concepts and recent advancements in these therapeutic strategies. Claudin18.2 (CLDN18.2), a specific tight junction protein isoform, is minimally expressed in normal gastric mucosa but aberrantly overexpressed in various cancers. It plays a key role in regulating tumor cell differentiation, proliferation, and migration, making it an attractive therapeutic target, especially in gastric cancer. Moreover, molecular imaging techniques such as immuno-positron emission tomography, immuno-single photon emission computed tomography, and near-infrared fluorescence imaging enable non-invasive evaluation of CLDN18.2 expression, improving diagnosis and guiding personalized treatment. This review summarizes recent advances in CLDN18.2-targeted therapies and molecular imaging for cancer management. We outline the biomarker’s biological functions and signaling pathways across cancers, highlighting the development of precision therapeutics. We also discuss applications and limitations of CLDN18.2-targeted theranostics in digestive malignancies and address clinical translation challenges and future directions. https://lnkd.in/eMK4E5Tx

🔬 CAR-γδ T Cells Targeting CLDN18.2: A Game-Changer for Solid Tumor Therapy? A new study presents CAR-γδ T cells targeting Claudin18.2 (CLDN18.2) as a novel strategy for treating gastric and pancreatic cancers. These cells demonstrate stronger tumor-killing capacity than conventional CAR-αβ T cells, offering a potential allogeneic, off-the-shelf solution for solid tumors. 1️⃣ Why γδ T Cells Over αβ T Cells? 🚀 MHC-independent targeting → No need for patient-specific HLA matching, making them ideal for allogeneic therapy. 🛡️ Better tumor infiltration → Unlike αβ T cells, γδ T cells are not restricted by immune-suppressive solid tumor microenvironments. ⚡ Dual targeting potential → Recognize CLDN18.2 while leveraging innate-like detection of stress ligands (NKG2D, BTN3A, MIC-A/B, ULBPs). 🩸 Lower risk of GvHD → Unlike αβ T cells, γδ T cells have reduced alloreactivity, making them safer for allogeneic applications. 2️⃣ Key Study Findings ✅ CLDN18.2 as a target → Highly expressed in gastric, pancreatic, and esophageal cancers, with low normal tissue expression. ✅ CAR-γδ T cell engineering → Lentiviral transduction used to generate CLDN18.2-CAR γδ T cells. ✅ Stronger tumor killing than αβ CAR-T → Enhanced secretion of Granzyme B, Perforin-1, and IFN-γ, boosting tumor lysis. ✅ In vivo efficacy → CAR-γδ T cells significantly reduced tumor burden and improved survival in xenograft models. ✅ Persistence & proliferation → Sustained expansion post-infusion, a key challenge for current CAR therapies in solid tumors. 3️⃣ Clinical Implications 💡 Potential for an off-the-shelf, allogeneic CAR-T product targeting solid tumors. 💡 Combination with checkpoint inhibitors or cytokines may further enhance anti-tumor efficacy. 💡 CLDN18.2 as a precision target → Opportunities for future clinical translation, including bispecific strategies. ❓ Could CAR-γδ T cells redefine immunotherapy for solid tumors? This study provides insights for next-generation cell therapies with greater efficacy, persistence, and accessibility. #CellTherapy #CART #Immunotherapy #Oncology #SolidTumors #GeneTherapy #CancerResearch

Claudins - The Next Big Solid Tumor Target? A major 2026 review in Nature Reviews Cancer dissects why CLDN proteins are rapidly emerging as precision oncology targets Here’s what every oncologist should know: 🧬 What are Claudins? Tight junction transmembrane proteins maintaining epithelial polarity. Frequently dysregulated and overexpressed across solid tumors. 🔥 Why they matter in cancer •Promote proliferation •Drive EMT & stemness •Modulate fibrosis •Shape immune microenvironment •Contribute to therapeutic resistance 🎯 Therapeutic breakthrough CLDN18.2 targeting has achieved regulatory approval - validating claudins as druggable surface antigens 🚀 Therapeutic platforms in development •Monoclonal antibodies •ADCs •Bispecific antibodies •CAR-T cells •Intracellular pathway targeting 🧠 Precision angle Surface overexpression + subtype correlation + biomarker-enriched selection = scalable solid tumor strategy. Claudins may follow the HER2 playbook. From barrier proteins to immunotherapy targets. 📖 Full review: Nature Reviews Cancer 2026

Claudin-18.2 is not expressed in normal tissues outside the stomach, I mean that its expression is highly restricted to the normal gastric epithelial cells lining the stomach in physiological conditions. This is unlike many other biomarkers, which may be found in a wide variety of normal tissues, potentially leading to off-target effects in therapy. Here’s why this matters: 1. Tissue-Specific Expression: Claudin-18.2 is specifically expressed in the tight junctions of gastric epithelial cells. In healthy individuals, it is not detectable in the epithelial cells of other organs, such as the intestines, liver, pancreas, or other normal tissues, under non-disease conditions. 2. Therapeutic Advantage: Because Claudin-18.2 is confined to the stomach lining in normal tissues, therapies targeting it (e.g., Zolbetuximab) are highly specific to gastric cancer cells, minimizing damage to normal, healthy tissues. This specificity reduces the risk of off-target toxicity, a common challenge in cancer therapy. 3. Metastatic Tumors: Even in metastatic gastric cancer, Claudin-18.2 often continues to be expressed, providing a reliable target for systemic therapies. However, in cancerous or metaplastic conditions, its expression pattern can become dysregulated and show up in tumors derived from gastric epithelium, which is why it serves as an excellent biomarker for diagnosing and targeting gastric cancer. #oncology #Gastriccancer #pathology #OncoDaily OncoDaily #pathologists Roche Middle East Burjeel Cancer Institute | BCI

The emergence of claudin 18.2-targeted therapies has sparked excitement in cancer research. Claudin 18.2, a protein expressed during malignant transformation, has become a focal point for innovative treatments. Clinical trials, notably SPOTLIGHT and GLOW, demonstrate the effectiveness of zolbetuximab, an anti-claudin 18.2 monoclonal antibody, in improving survival outcomes when combined with chemotherapy for advanced gastric cancer. Beyond zolbetuximab, ongoing trials explore various modalities targeting claudin 18.2, such as newer antibodies, bispecific antibodies, antibody–drug conjugates, and claudin 18.2-specific CAR T cells. This diverse approach signifies a paradigm shift in cancer therapy, offering promise for improved outcomes across a spectrum of solid tumors expressing claudin 18.2. https://t.co/AfPrmRJTNS

An Innovative Approach #AACR25 Abstract #4807 presents a novel strategy to overcome EGFR-TKI resistance in NSCLC by targeting Claudin-3 (CLDN3) with CAR-T cells. CLDN3 is frequently overexpressed in EGFR-mutant tumors following TKI treatment, as revealed by scRNA-seq analysis presented in the study, and, due to its nature as a tight junction protein, has been considered a challenging target for conventional antibody-based CAR designs. To address this, the researchers employed the C-terminal domain of Clostridium perfringens enterotoxin (cCPE) as the antigen recognition domain of their CAR construct. cCPE has been well characterized for its high-affinity and subtype-selective binding to CLDN3 and CLDN4 through extracellular loop interactions, making it a compelling alternative to traditional antibody-based binders. Among various truncations tested, the aa184–319 segment (C3M) demonstrated the highest specificity and binding affinity for CLDN3. CAR-T cells engineered with this domain exhibited potent cytotoxicity across multiple EGFR-mutant and TKI-resistant models and showed significant tumor regression in in vivo xenograft systems. https://lnkd.in/ghHQ_qaT

From their abstract: In the past few decades, increasing efforts to exploit claudins in cancer therapy have led to the development of targeted molecules, including zolbetuximab, a first-in-class CLDN-18.2-targeted antibody for the treatment of gastric cancer, which has been recently approved by the United States Food and Drug Administration. This milestone emphasizes the therapeutic potential of targeting this protein family and its possible role in expanding treatment options for cancer. In this review, we discuss the evolving landscape of claudin-targeting therapeutics, examining key advances, emerging challenges and future prospects.