Claudin is a four-transmembrane protein that connects cells to each other [1]. It stabilizes the polarity of epithelial cells, and regulates cell permeability. (Figure 1)

Figure 1. The structure of claudin protein. It contains four transmembrane domains (TMDs) and two extracellular loops (ECLs).

Claudin-18 has two isoforms, Claudin-18.1 and Claudin-18.2(CLDN18.2). Claudin-18.1 is expressed in alveolar epithelial cells, while claudin-18.2 is a gastric epithelial cell-specific marker and it is only expressed in gastric glands of mature gastric epithelial cells [2].

Claudin 18.2 expression is significantly upregulated in a variety of tumors, such as gastric cancer (53.0–87.0%) [3,4], esophageal cancer (18.4%~50%)[5], lung cancer (7.78%)[6], and pancreatic cancer (59.2%)[7]. Its high expression in gastric cancer makes it a possible new target for gastric cancer treatment.

In normal gastric epithelial cells, Claudin-18.2 is hidden inside the cell and cannot be detected by antibodies. When gastric epithelial cells undergo malignant transformation, cell polarity is destroyed and Claudin-18.2 epitopes are exposed [8]. Therefore, Claudin-18.2 can not only be used as a diagnostic indicator for gastric cancer, but also as a target for the treatment of gastric cancer.

On October 18, 2024, the Food and Drug Administration approved zolbetuximab-clzb (Vyloy, Astellas Pharma US, Inc.), a claudin 18.2 (CLDN18.2)-directed cytolytic antibody, with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test.[9]

In December 2024, National Comprehensive Cancer Network (NCCN) guidelines of the United States [10] officially included zolbetuximab combined with chemotherapy as a preferred option for the first-line treatment of advanced gastric cancer. All gastric cancer patients should undergo Claudin18.2 testing.

We, Dartmon, provide Claudin18.2 antibody for IHC test.

It should be interpreted as negative result if Claudin-18.2 presents cytoplasmic granular staining.

Claudin-18.2 diagnosis results classification is according to the intensity of cell membrane staining. 0 means no staining; 1+ means weak positive; 2+ means moderate positive; and 3+ means strong positive. It should be notice that Claudin-18.2 has a high degree of intratumor heterogeneity, with different staining intensities in the same tumor area.

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References

[1] CAO W, XING H, LI Y, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy[J]. Biomarker Research, 2022, 10(1): 38. DOI: 10.1186/s40364-022-00385-1.

[2] TÜRECI O, KOSLOWSKI M, HELFTENBEIN G, et al. Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals[J]. Gene, 2011, 481(2): 83-92. DOI: 10.1016/j.gene.2011.04.007.

[3] SAHIN U, KOSLOWSKI M, DHAENE K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development[J]. Clinical Cancer Research, 2008, 14(23): 7624-7634. DOI: 10.1158/1078-0432.CCR-08-1547.

[4] LU Y, WU T, SHENG Y, et al. Correlation between Claudin-18 expression and clinicopathological features and prognosis in patients with gastric cancer[J]. Journal of Gastrointestinal Oncology, 2020, 11(6): 1253-1260. DOI: 10.21037/jgo-20-463.

[5] MOENTENICH V, GEBUER F, COMUT E, et al. Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies[J]. Oncology Letters, 2020, 19(6): 3665-3670. DOI: 10.3892/ol.2020.11520.

[6] LIU J, YANG H, YIN D, et al. Expression and prognostic analysis of CLDN18 and Claudin18.2 in lung adenocarcinoma[J]. Pathology Research and Practice, 2022, 238: 154068. DOI: 10.1016/j.prp.2022.154068.

[7] KYUNO D, TAKASAWA A, TAKASAWA K, et al. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials[J]. Tissue Barriers, 2022, 10(1): 1967080. DOI: 10.1080/21688370.2021.1967080.

[8] MATHIAS-MACHADO M C, DE JESUS V H F, JÁCOME A, et al. Claudin 18.2 as a New Biomarker in Gastric Cancer—What Should We Know?[J]. Cancers, 2024, 16(3): 679. DOI: 10.3390/cancers16030679.

[9] https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma

[10] National Comprehensive Cancer Network (NCCN) guideline Version5.2024 Gastric Cancer.