CLDN18

Official Full Name

claudin 18

Organism

Homo sapiens

GeneID

51208

Background

This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. This gene is upregulated in patients with ulcerative colitis and highly overexpressed in infiltrating ductal adenocarcinomas. PKC/MAPK/AP-1 (protein kinase C/mitogen-activated protein kinase/activator protein-1) dependent pathway regulates the expression of this gene in gastric cells. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jun 2010]

Synonyms

SFTA5; SFTPJ;

Protein Sequence

MSTTTCQVVAFLLSILGLAGCIAATGMDMWSTQDLYDNPVTSVFQYEGLWRSCVRQSSGFTECRPYFTILGLPAMLQAVRALMIVGIVLGAIGLLVSIFALKCIRIGSMEDSAKANMTLTSGIMFIVSGLCAIAGVSVFANMLVTNFWMSTANMYTGMGGMVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLAPEETNYKAVSYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDYV

Open

Disease

Adenocarcinoma, Esophageal cancer, Oesophagogastric junction cancer, Pancreatic cancer, Solid tumour/cancer, Stomach cancer, Stomach cancer

Approved Drug

Clinical Trial Drug

10 +

Discontinued Drug

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Detailed Information

Human Claudin-18 gene is found in chromosomal region 3q22.3 and generates two major protein isoforms via alternative splicing: Claudin-18.1 and Claudin-18.2. Whereas Claudin-18.2 is found in gastric epithelial cells, Claudin-18.1 is mostly expressed in alveolar epithelial cells. Variations in the amino-terminal sequences of the two isoforms explain their differing purposes in various tissues. Through control of intercellular permeability in the gastric mucosa, Claudin-18.2 functions as a barrier stopping stomach acid leakage.

Tight junctions formed between cells by members of the Claudin protein family govern permeability and so the movement of tiny molecules such as water and electrolytes is regulated. Like other transmembrane proteins, Claudin-18's cytoplasmic terminus interacts via the PDZ domain with the cytoskeleton and signaling pathway proteins to produce persistent cell connections. Along with preserving intercellular barrier function, this helps with polarity maintenance and signal transmission.

Functions and Biological Roles of Claudin-18

Particularly in maintaining epithelial barrier function and affecting tumor formation, Claudin-18 is crucial in many physiological processes. In alveolar epithelial cells, Claudin-18.1 expression is essential; its absence may cause abnormalities in lung shape and function, as seen in pulmonary fibrosis and chronic obstructive pulmonary disease (COPD), when Claudin-18.1 levels considerably decline.

Mostly serving the epithelial tissues of the digestive system, including the stomach and esophagus, Claudin-18.2 is highly important for preserving gastric acid barrier function. Claudin-18.2 lowers intercellular permeability in gastric mucosal cells, therefore reducing leak of H+ ions from stomach acid via paracellular channels and so shielding the gastrointestinal lining from acid erosion. Studies show that Claudin-18.2 can be controlled throughout the growth of stomach and esophageal tumors; its aberrant expression is strongly associated with tumor cell proliferation, metastases, and invasiveness.

Furthermore intimately related to bone metabolism and immunological responses, Claudin-18 is engaged in controlling many cellular signaling pathways including calcium signaling and RANKL-induced osteoclast differentiation. Often resulting in dysregulated cell adhesion, loss or aberrant expression of Claudin-18 influences tissue form and function, therefore influencing the start of a disease.

Expression and Functional Disruption of Claudin-18 in Tumors

Altered expression of Claudin-18 in malignancies, especially gastric, esophageal, and pancreatic cancers, supports its target status for cancer therapy. Whereas Claudin-18.2 is commonly increased in tumor cells, in normal tissues it is mostly restricted to stomach mucosal epithelial cells. Research on Claudin-18.2 mRNA expression levels in malignant tissues compared to normal tissues has shown typically decreased levels presumably resulting from genomic methylation alterations. Correspondingly, the intercellular connections in tumor cells are disturbed and cell polarity is lost, suggesting a possible crucial function for Claudin-18.2 in epithelial-mesenchymal transition (EMT) in malignancies.

Although Claudin-18's expression dysregulation is still a major feature of carcinogenesis, gene mutations of this gene are rare in tumor tissues. For example, overexpression of Claudin-18 in esophageal and pulmonary squamous cell carcinoma might be intimately correlated with tumor invasiveness and metastases. Furthermore, Claudin-18 may have interchromosomal translocation with other genes, including ARHGAP26, boosting tumor cell motility and invasiveness.

The Potential of Claudin-18.2 as a Therapeutic Target

The specific expression of Claudin-18.2 makes it an ideal cancer target, especially for gastric, esophageal, and pancreatic cancers. Since Claudin-18.2 is minimally expressed or inaccessible in normal tissues, targeting this antigen can avoid harming normal tissues, offering good selectivity and lower toxicity.

Figure 1 illustrates how CLDN18.2-targeted monoclonal antibodies and CAR-T cells bind selectively to CLDN18.2-expressing tumor cells, triggering mechanisms that lead to cell lysis. Figure 1. Mechanisms of CLDN18.2-targeted monoclonal antibody intervention and CAR T cell interaction. (Chen J, et al., 2023)

Monoclonal antibodies, antibody-drug conjugates (ADCs), bispecific antibodies, and CAR-T cell treatments make up Claudin-18.2's current targeting plans. The first clinically tested antibody aimed against Claudin-18.2, zolbetuximab (IMAB362), shows excellent effectiveness in treating esophageal and stomach malignancies. This antibody increases immune detection and clearance of tumor cells by means of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

Furthermore, ADCs and bispecific antibodies show great promise in clinical research. Two ADCs aiming against Claudin-18.2, CPO102, and SOT102, for instance, provide chemotherapeutic medicines more specifically to tumor cells, thereby greatly improving the therapy's effectiveness. Further enhancing immunotherapy results is the ability of bispecific antibodies such as anti-CD3 x Claudin-18.2 to guide T cells toward an assault on tumor cells.

Preclinical Studies and Outlook

Although Claudin-18.2 has great promise for cancer treatment, therapeutic use of it still presents difficulties. First, with only a few amino acid variations, the structural closeness between Claudin-18.2 and Claudin-18.1 presents a difficulty in producing highly specific anti-Claudin-18.2 antibodies. Second, even if preclinical studies show the high effectiveness of Claudin-18.2-targeted treatments, further confirmation of efficacy and safety in useful applications is required.

Deeper knowledge of the mechanistic functions and creative therapeutic approaches of Claudin-18.2 makes it probable that this target for cancer therapy will be more often used in the future. In the framework of precision medicine, its targeted therapy in malignant tumors including gastric, esophageal, and pancreatic malignancies may provide fresh therapeutic alternatives for more patients.

References:

Chen J, Xu Z, et al. Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications. Front Oncol. 2023 Mar 10;13:1132319.
Cao W, Xing H, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res. 2022 May 31;10(1):38.
Mathias-Machado MC, de Jesus VHF, et al. Claudin 18.2 as a New Biomarker in Gastric Cancer-What Should We Know? Cancers (Basel). 2024 Feb 5;16(3):679.

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