Claudin 18.2 (CLDN18.2) is a specialized protein that has emerged as a target in the treatment of certain advanced cancers. This protein is an isoform of the claudin family, which are transmembrane proteins crucial for cell-to-cell adhesion. CLDN18.2 is a selective biomarker whose presence is mainly restricted to the stomach lining in healthy individuals. Its unique expression pattern makes it an ideal feature for targeted therapeutic development in oncology, representing an advancement in precision medicine for gastrointestinal malignancies.
The Normal Role of Claudin 18.2 in Healthy Tissue
Claudins are the primary components of tight junctions, which create a seal between epithelial cells. These tight junctions function as a paracellular barrier, controlling the passage of molecules between cells and helping to maintain cell layer polarity. The CLDN18.2 isoform is almost exclusively expressed on the differentiated cells lining the gastric mucosa, or stomach wall. Its role is to protect the underlying tissue from the highly acidic environment required for digestion by forming a barrier that prevents the passive leakage of hydrogen ions (H+) from the gastric lumen. In this healthy, polarized state, the portion of the CLDN18.2 protein targeted by drugs is sequestered within the tight junction complex, making its binding domains inaccessible to the bloodstream or to any circulating therapeutic agents.
Aberrant Expression in Gastrointestinal Cancers
CLDN18.2 becomes a viable target in cancer due to a change in cellular organization during malignant transformation. In healthy cells, the protein is tucked away within the tight junction, but when cancer develops, the epithelial cells lose their normal polarity. This loss of organization causes the tight junctions to break down. As the tumor cells become disorganized, the CLDN18.2 protein is no longer confined to the junctional complex and becomes exposed on the entire surface of the cancer cell membrane. This exposure of the extracellular domain transforms CLDN18.2 from a sequestered protein into an accessible target for therapy, a mislocalization commonly observed in gastric adenocarcinoma, cancer of the gastroesophageal junction, and certain pancreatic cancers.
The prevalence of CLDN18.2 expression varies across tumor types. A significant portion of gastric and gastroesophageal junction cancers test positive, often reported to be around 40% in advanced cases. Expression is also found in a subset of pancreatic adenocarcinomas, with positivity rates reported around 16.7%. This restriction of CLDN18.2 to the gastric mucosa in healthy tissue provides a wide therapeutic window where drugs can target cancer cells while sparing most other organs.
Current Treatment Strategies Targeting Claudin 18.2
The exposed CLDN18.2 protein has led to the development of several targeted treatment modalities. The most clinically advanced are monoclonal antibodies, which function by directly binding to the exposed protein. Zolbetuximab, a chimeric IgG1 monoclonal antibody, has received regulatory approval for CLDN18.2-positive gastric and gastroesophageal junction adenocarcinoma.
When zolbetuximab binds to the CLDN18.2 protein, it triggers an immune response through two primary mechanisms. One is antibody-dependent cellular cytotoxicity (ADCC), where immune cells are recruited to recognize and destroy the antibody-coated cancer cell. The other is complement-dependent cytotoxicity (CDC), where the binding antibody activates a cascade of plasma proteins that ultimately leads to the lysis, or rupture, of the cancer cell membrane. Clinical trials, such as GLOW and SPOTLIGHT, have demonstrated that adding zolbetuximab to standard chemotherapy improves survival outcomes in patients with CLDN18.2-positive, HER2-negative tumors.
Antibody-Drug Conjugates (ADCs)
Antibody-Drug Conjugates (ADCs) act like guided missiles to deliver a chemotherapy payload directly to the tumor. An ADC consists of a CLDN18.2-targeting antibody linked to a highly potent cytotoxic agent, such as a Topoisomerase inhibitor or a microtubule-disrupting agent. Once the antibody binds to CLDN18.2, the entire complex is internalized by the cancer cell, releasing the toxic drug inside and causing cell death. This approach minimizes systemic exposure to the potent chemotherapy, reducing damage to healthy tissues.
Emerging Platforms
Researchers are exploring other platforms, including bispecific antibodies and CAR T-cells. Bispecific antibodies are engineered to bind simultaneously to CLDN18.2 on the tumor cell and an immune-activating molecule on a T-cell, effectively bridging the two to enhance immune-mediated destruction. Chimeric Antigen Receptor (CAR) T-cell therapy involves genetically modifying a patient’s own T-cells to recognize and attack CLDN18.2-expressing tumor cells, representing an emerging frontier in cellular immunotherapy.
Testing and Identification of CLDN18.2 Status
The use of CLDN18.2-targeted therapies requires the identification of patients whose tumors express the protein. This selection relies on a diagnostic test performed on a sample of the tumor tissue. The standard method for determining CLDN18.2 status is Immunohistochemistry (IHC), a technique that uses specific antibodies to stain for the protein within the tissue sample. Pathologists evaluate the IHC staining based on two criteria: the intensity of the membrane staining and the percentage of tumor cells that express the protein. For a tumor to be considered positive and eligible for treatment, it must meet a specific companion diagnostic cutoff, defined as having moderate-to-strong (2+ or 3+ intensity) membranous staining in at least 75% of the viable tumor cells.