Gastric cancer, or stomach cancer, is a significant global health challenge. Cancer treatment has evolved towards more precise, individualized methods. Modern oncology identifies specific molecular features, known as biomarkers, on cancer cells to guide therapeutic decisions, tailoring treatments to a patient’s tumor.
Understanding the Claudin 18.2 Protein
Claudin 18.2 (CLDN18.2) is a protein involved in the normal functioning of the stomach lining. It belongs to a family of proteins that form “tight junctions,” which act like a seal between cells, creating a protective barrier in the stomach.
These tight junctions regulate the passage of molecules between cells, maintaining the stomach’s protective barrier. This barrier prevents stomach acid from leaking into surrounding tissues. CLDN18.2 is found almost exclusively in the differentiated epithelial cells lining the stomach mucosa.
Claudin 18.2 as a Cancer Biomarker
When gastric cells undergo malignant transformation, the stomach lining’s organized structure can become disrupted. This disruption exposes the CLDN18.2 protein on the surface of cancer cells, where it is typically hidden within healthy tight junctions.
The presence of CLDN18.2 on the outer surface of these cancer cells makes it a promising and distinct target for therapies. This protein is highly specific to stomach tissue in its normal state, offering a unique opportunity for targeted intervention when exposed on cancerous cells. Not all gastric cancers exhibit this feature, identifying a specific disease subtype.
Studies indicate that CLDN18.2 positivity, defined by moderate-to-strong expression, is found in a notable proportion of gastric tumor samples, ranging from approximately 24% to 83% across different studies. For instance, some research suggests that around 38% to 51% of gastric adenocarcinomas may be CLDN18.2-positive using a common definition.
Testing for Claudin 18.2 Expression
To determine if a gastric tumor expresses CLDN18.2, a pathologist analyzes a tissue sample obtained through a biopsy. Immunohistochemistry (IHC) is the primary method for this assessment.
During IHC, a specialized antibody designed to recognize and bind specifically to the CLDN18.2 protein is applied to the tumor tissue. If CLDN18.2 is present, the bound antibodies trigger a chemical reaction that causes the cells to change color. This color change allows pathologists to visualize the protein’s presence and evaluate its intensity and distribution.
A tumor is considered “CLDN18.2-positive” if at least 75% of the tumor cells show moderate-to-strong membranous staining. Testing can be performed on samples from both primary gastric tumors and metastatic lesions, as CLDN18.2 expression is often maintained during cancer spread.
Therapeutic Strategies Targeting Claudin 18.2
Targeting CLDN18.2 offers new avenues for treating gastric cancer in patients whose tumors express this protein. The primary therapeutic approach involves the use of monoclonal antibodies. These laboratory-engineered antibodies are designed to selectively attach to the exposed CLDN18.2 protein on the surface of cancer cells.
Zolbetuximab, known by its brand name Vyloy, is a notable monoclonal antibody that targets CLDN18.2. Once Zolbetuximab binds to CLDN18.2 on the cancer cell, it initiates immune responses to destroy the tumor. This includes antibody-dependent cellular cytotoxicity (ADCC), where the antibody flags the cancer cell for destruction by immune cells like natural killer (NK) cells.
The antibody also triggers complement-dependent cytotoxicity (CDC), another immune mechanism that directly damages and eliminates cancer cells. This dual mechanism means Zolbetuximab not only marks cancer cells for immune attack but can also directly disrupt their membranes, leading to cell death.
These targeted therapies are commonly administered in combination with traditional chemotherapy regimens, rather than as standalone treatments. Clinical trials like SPOTLIGHT and GLOW have demonstrated that combining Zolbetuximab with chemotherapy, such as mFOLFOX6 or CAPOX, improves patient outcomes. These combinations have shown enhanced progression-free survival (the time a patient lives without the cancer worsening) and overall survival compared to chemotherapy alone.
For instance, in the SPOTLIGHT trial, Zolbetuximab combined with mFOLFOX6 extended median progression-free survival to 10.61 months compared to 8.67 months with chemotherapy alone. Similarly, overall survival was prolonged to 18.23 months versus 15.54 months in the respective groups.
Beyond monoclonal antibodies, other therapeutic strategies targeting CLDN18.2 are under investigation. Chimeric Antigen Receptor (CAR) T-cell therapy is one such emerging approach. In this therapy, a patient’s own T-cells are genetically modified in the lab to recognize and attack cancer cells expressing CLDN18.2.
Early-phase clinical trials of CLDN18.2-specific CAR-T cells have shown promising results in patients with advanced gastric and pancreatic adenocarcinomas. These studies have reported objective responses and manageable safety profiles, including cytokine release syndrome, which is a common side effect of CAR-T therapy. This ongoing research continues to explore new ways to leverage CLDN18.2 as a therapeutic target.