CLAUDIN18.2

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

Biology

  • The wild-type CLDN18 gene locus encodes the protein CLAUDIN-18, a tight junction (TJ)protein and a member of the claudin family.1,2
  • CLAUDIN18.2 (CLDN18.2) is a specific splice isoform of the claudin-18 protein and is expressed primarily in gastric epithelial cells, with minimal expression in other healthy tissues.1,2
  • In healthy tissues, CLAUDIN proteins are localized at the apical region of the cell membrane, where they function within the TJ complex to promote cell adhesion; maintain cell polarity; and facilitate cell migration, matrix remodeling, and proliferation.3
  • Under normal physiological conditions, CLDN18.2 is shielded from epitope exposure. However, during malignant cellular transformation, alterations in cell polarity result in the exposure of CLDN18.2 epitopes on the cell surface, making it a viable target for molecular therapy.1,2

Etiology and Epidemiology

  • CLDN18.2 overexpression, defined as moderate-to-strong CLDN18.2 membrane staining in ≥75% of tumor cells, occurs in approximately 20-30% of gastric and gastroesophagealjunction (GEJ) cancers.4
  • Altered CLDN18.2 expression can impair tight junction integrity, leading to increased permeability and facilitating processes like epithelial-mesenchymal transition (EMT), which enhances tumor invasiveness and metastatic potential.5
  • CLDN18.2 has also been implicated in various oncogenic signaling pathways, including SPAK-p38 MAPK, EGFR-ERK, and protein kinase C.2

CLAUDIN18.2 Testing

When to Test:

  • Universal testing for microsatellite instability (MSI) status by polymerase chain reaction (PCR)/next-generation sequencing (NGS) or mismatch repair (MMR) status by immunohistochemistry (IHC) is recommended in all patients with newly diagnosed gastric or GEJ adenocarcinoma.
  • Human epidermal growth factor 2 (HER2), programmed death ligand 1 (PD-L1), and CLDN18.2 testing are recommended at the time of diagnosis if advanced/metastatic disease is documented or suspected.6
  • Testing for CLDN18.2 should take place prior to the commencement of targeted therapy, as this will determine whether the patient is eligible for treatment with zolbetuximab.6,7

Available Testing Methods:

  • IHC is the primary testing method used to evaluate CLDN18.2 status in tumor samples.2,6
  • The Ventana CLDN18 (43-14A) RxDx IHC Assay is the FDA-approved companion diagnostic for detecting CLDN18.2 expression and was utilized in the SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials to identify patients for zolbetuximab therapy.6,8-10

Testing Guideline Recommendations:

  • The NCCN recommends CLDN18.2 testing for patients for whom zolbetuximab is being considered.6
  • IHC/ISH/targeted PCR are the preferred initial approaches to assessing biomarkers. However, NGS testing through a Clinical Laboratory Improvement Amendments–approved lab may be considered later in the clinical course for patients with sufficient tumor tissue available for testing.6
Figure

CLAUDIN18.2 Targeted Therapy

Approved Agent(s):

  • One oral agent, zolbetuximab (Vyloy), has been approved and is the first monoclonal antibody directed against CLDN18.2.7,8

Zolbetuximab:

  • FDA-Approved Indication:
    • Zolbetuximab is indicated for use in combination with fluoropyrimidine-and platinum-based chemotherapy for the treatment of adult patients with locally advanced, unresectable or metastatic CLDN18.2-positive, HER2-negative gastric or GEJ adenocarcinoma.7
  • Mechanism of Action:
    • Zolbetuximab binds specifically to the extracellular domain of CLDN18.2, triggering antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).7
  • Drug Information:
  • Patient Resources:

References

  1. Fassan M, Kuwata T, Matkowskyj KA, Röcken C, Rüschoff J. Claudin-18.2 immunohistochemical evaluation in gastric and gastroesophageal junction adenocarcinomas to direct targeted therapy: a practical approach. Modern Pathology. 2024;37(11):100589. doi:10.1016/j.modpat.2024.100589
  2. Cao W, Xing H, Li Y, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomarker Research. 2022;10(1):38. doi:10.1186/s40364-022-00385-1
  3. Mathias-Machado MC, de Jesus VHF, Jácome A, et al. Claudin 18.2 as a biomarker in gastric cancer—what should we know? Cancers. 2024;16(3):679. doi:10.3390/cancers16030679
  4. Pellino A, Riello E, Nappo F, et al. Targeted therapies in metastatic gastric cancer: current knowledge and future perspectives. World J Gastroenterol. 2019;25(38):5773-5788. doi:10.3748/wjg.v25.i38.5773
  5. Hong JY, An JY, Lee J, et al. Claudin18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer. Transl Cancer Res. 2020;9(5):3367-3374. doi:10.21037/tcr-19-1876
  6. NCCN Clinical Practice Guidelines. Gastric cancer, version 1.2025. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  7. Vyloy (zolbetuximab-Clzb). Prescribing information. Astellas Pharma US, Inc; 2024. Accessed March 3, 2025. https://www.astellas.com/us/system/files/vyloy_pi.pdf
  8. FDA Approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA.gov. Updated October 18, 2024. Accessed March 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma
  9. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7
  10. Shitara K, Van Cutsem E, Lordick F, et al. Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 18 isoform 2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. JCO. 2024;42(suppl 16):4036-4036. doi:10.1200/JCO.2024.42.16_suppl.4036