CLAUDIN18.2

  • CLAUDIN18.2 (CLDN18.2)
  • Gene location: Chromosome 3q22.3

Biology

  • CLDN18.2 is a gastric-specific isoform of the tight junction protein claudin-18, which is involved in cell polarity and barrier function.1
  • Specifically confined to the gastric mucosa, CLDN18.2 becomes exposed to the surface of tumor cells following malignant transformation, thereby becoming an ideal target.1
  • It is not highly expressed in most normal tissues but is aberrantly expressed in a few malignancies, including pancreatic cancer.1-3
  • CLDN18.2 gets exposed to cancer cells but is still well hidden in normal tissue, making it a good target for antibody treatments.1,2
  • CLDN18.2-expressing tumors can be a distinctive biological subtype of pancreatic ductal adenocarcinoma (PDAC).3

Etiology and Epidemiology

  • CLDN18.2 occurs in approximately 25% of pancreatic cancer, both metastatic and primary.2,3
  • Its PDAC expression is typically heterogeneous and can be associated with more aggressive disease features.3
  • Increased CLDN18.2 expression has been associated with lymph node metastasis and more advanced-stage disease.3,5

Testing

When to Test:

  • While not currently part of standard of care testing, CLDN18.2 evaluation is increasingly performed in patients with advanced or metastatic PDAC to determine eligibility for clinical trials involving investigational therapies.2,4

Available Testing Methods:

  • Immunohistochemistry (IHC) testing is the primary modality to evaluate CLDN18.2 status.2,3,6
  • Tumors are generally considered positive when ≥ 50% of cells show moderate to strong membrane staining or when using a ≥ 2+ staining intensity threshold.2
  • Testing is typically performed on biopsy or archived tissue samples.2

Guideline Recommendations:

  • Current National Comprehensive Cancer Network guidelines do not mandate CLDN18.2 testing in pancreatic cancer.6
  • However, increased trial activity is expanding the role of IHC screening for this marker in eligible patients.4,5

Targeted Therapy

Approved Agents:

  • No FDA-approved therapies exist for CLDN18.2 in pancreatic cancer up to 2024.6

Investigational Agents:

  • Zolbetuximab (IMAB362)
    • Chimeric monoclonal antibody that selectively targets CLDN18.2.2-4
    • Demonstrated activity in gastric/gastroesophageal cancers and is under investigation for PDAC.4,5
    • Preliminary data show clinical activity in highly CLDN18.2-expressing PDAC tumors.4,7
  • Mechanism of Action
    • Zolbetuximab immunoglobulin G1 monoclonal antibody binds specifically to CLDN18.2, making it a highly selective therapeutic agent.2-4
    • Zolbetuximab induces death of tumor cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.2-4
    • Lower expression of CLDN18.2 in normal tissues minimizes off-target toxicity. 2-4
  • Investigational Studies
    • Phase 1/2 trial7
      • ClinicalTrials.gov: NCT03816163
      • Study design: Phase 1/2 open-label study assessing zolbetuximab with nab-paclitaxel and gemcitabine in patients with CLDN18.2-positive PDAC.

References

  1. Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008;14(23):7624-7634. doi:10.1158/1078-0432.CCR-08-1547
  2. Valentini AM, Arborea G, Grassi I, et al. Claudin 18.2: an attractive marker in pancreatic ductal adenocarcinoma. Oncol Lett. 2025;29(3):140. doi:10.3892/ol.2025.14886
  3. Arseneau RJ, Kempster E, Bekkers C, et al. Claudin 18 (43-14A clone) expression in pancreatic ductal adenocarcinoma: assessment of a potential clinical biomarker for zolbetuximab therapy. Transl Oncol. 2025;55:102362. doi:10.1016/j.tranon.2025.102362
  4. Results from Astellas’ phase 3 SPOTLIGHT trial of investigational zolbetuximab published in The Lancet. News release. Astellas Pharma Inc. April 14, 2023. Accessed June 17, 2025. https://www.astellas.com/en/system/files/news/2023-04/20230417_en_1.pdf
  5. Türeci Ӧ, Mitnacht-Kraus R, Wöll S, Yamada T, Sahin U. Characterization of zolbetuximab in pancreatic cancer models. Oncoimmunology. 2018;8(1):e1523096. doi:10.1080/2162402X.2018.1523096
  6. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 1.2024. Accessed June 11, 2025. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  7. A study of zolbetuximab (IMAB362) in adults with pancreatic cancer. ClinicalTrials.gov. Updated April 27, 2025. https://clinicaltrials.gov/study/NCT03816163