Claudin 18.2 is a protein belonging to the claudin family. These proteins form specialized connections between cells, maintaining tissue integrity. This sets the stage for recognizing its involvement in both healthy processes and disease states.
The Normal Function of Claudin 18.2
In a healthy body, claudin 18.2 is a component of “tight junctions,” abundant in the stomach lining. These junctions form a protective, leak-proof barrier, preventing substances from passing between cells.
This barrier function is important in the stomach, which contains highly acidic gastric juices. Tight junctions, reinforced by claudin 18.2, seal the spaces between epithelial cells lining the stomach. This prevents harsh acids and digestive enzymes from leaking into underlying tissues, ensuring the stomach’s integrity.
Claudin 18.2 in Cancer Development
While claudin 18.2 normally resides deep within the tight junctions of healthy stomach cells, its specific binding sites are typically hidden and inaccessible. However, during the malignant transformation of cells, particularly in gastric, gastroesophageal junction, and pancreatic cancers, the normal cell structure can become disrupted.
This disruption causes claudin 18.2 to become abnormally exposed on the outer surface of these cancer cells. Its appearance on the cell surface transforms it into a distinct biomarker, distinguishing cancerous cells from healthy ones. This unique exposure makes claudin 18.2 an appealing target for therapeutic interventions, as it offers a way to selectively address cancer cells while minimizing impact on healthy tissues.
Therapies Targeting Claudin 18.2
The abnormal exposure of claudin 18.2 on cancer cell surfaces has led to the development of targeted therapies. Targeted therapy is a type of cancer treatment that uses drugs designed to identify and attack cancer cells based on their specific molecular characteristics, rather than broadly affecting all rapidly dividing cells like traditional chemotherapy. This approach aims to reduce harm to healthy cells.
A primary class of drugs developed to target claudin 18.2 are monoclonal antibodies. These are engineered antibodies specifically designed to recognize and bind to the exposed claudin 18.2 protein on the surface of tumor cells. Once an antibody binds to the cancer cell, it can activate immune responses to help destroy the cell.
For example, zolbetuximab is a monoclonal antibody that selectively binds to claudin 18.2-expressing cells. This binding initiates two main mechanisms: antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In ADCC, the antibody acts as a bridge, recruiting immune cells like natural killer (NK) cells to recognize and kill the targeted cancer cell. In CDC, the antibody binding activates the complement system, a part of the immune system, which then forms a membrane attack complex on the cancer cell surface, creating pores that lead to cell lysis and destruction.
Beyond monoclonal antibodies, other innovative therapeutic approaches are being explored. Chimeric Antigen Receptor T-cell (CAR-T) therapy is one such area of research. In CAR-T therapy, a patient’s own T-cells, a type of immune cell, are genetically modified in a laboratory to express a specialized receptor that recognizes claudin 18.2. These engineered CAR-T cells are then multiplied and infused back into the patient, where they can seek out and destroy cancer cells expressing claudin 18.2. Early studies for claudin 18.2-specific CAR-T cells in advanced gastric and pancreatic cancers have shown promising results, including objective responses and disease control.
Identifying Claudin 18.2 Expression in Patients
Before a patient can receive a claudin 18.2-targeted therapy, their tumor must undergo testing to confirm the presence and level of the protein. This diagnostic step is a cornerstone of personalized medicine, ensuring that treatments are matched to the specific biological characteristics of an individual’s cancer. The standard method for this evaluation is immunohistochemistry (IHC).
During IHC, a sample of tumor tissue, typically obtained through a biopsy, is prepared and then exposed to special antibodies that bind to claudin 18.2. These antibodies are linked to a detectable label, often a color-producing enzyme. A pathologist then examines the stained tissue under a microscope to determine if claudin 18.2 is present on the cancer cells and to what extent, often assessing both the intensity of the staining and the percentage of tumor cells expressing the protein. For instance, a common threshold for determining positivity for therapies like zolbetuximab is moderate-to-strong membranous staining in at least 75% of tumor cells. This diagnostic information guides treatment decisions, confirming that the patient’s cancer is a suitable target for claudin 18.2-directed therapies.