Claudin-18.2 (CLDN18.2) is a protein that has recently gained significant attention in the field of cancer research. It represents a specific target for developing new therapies against various malignancies. Scientists are exploring ways to precisely target this protein, aiming to deliver more effective treatments.
The Role of CLDN18.2 in the Body
CLDN18.2 is a component of tight junctions, which are specialized structures that connect cells in epithelial and endothelial tissues. These junctions form a barrier, regulating what passes between cells and maintaining tissue integrity.
In healthy individuals, CLDN18.2 is primarily found in the lining of the stomach, specifically in differentiated epithelial cells of the gastric mucosa. Here, it helps regulate cell differentiation and prevents gastric acid from leaking from the stomach lumen into surrounding tissues.
Under normal conditions, CLDN18.2 is largely hidden within these tight junctions, making it inaccessible to substances circulating in the bloodstream, including potential therapeutic agents. Its location deep within the cell membrane structure ensures it is shielded from the body’s immune system.
CLDN18.2 Expression in Cancer
The behavior of CLDN18.2 changes significantly in the context of cancer. While it is typically sequestered within tight junctions in healthy stomach cells, the disordered and rapid growth of cancer cells can disrupt these cellular connections. This disruption leads to the abnormal exposure of the CLDN18.2 protein on the surface of tumor cells.
This abnormal surface exposure transforms CLDN18.2 into a distinct marker for certain cancer types. Its expression can be significantly elevated in tumor tissues compared to normal tissues. This phenomenon is observed in several malignancies, including gastric (stomach) cancer, gastroesophageal junction (GEJ) cancer, and pancreatic cancer. CLDN18.2 is also found in metastatic lesions, such as lymph nodes and liver metastases, further indicating its relevance in advanced disease.
The presence of CLDN18.2 on the surface of cancer cells, rather than hidden within tight junctions, makes it an attractive target for therapeutic intervention. This unique presentation allows scientists to develop treatments that can specifically recognize and bind to cancer cells, distinguishing them from most healthy cells.
Therapeutic Strategies Targeting CLDN18.2
The unique exposure of CLDN18.2 on cancer cell surfaces has led to the development of several innovative therapeutic strategies. These approaches aim to selectively target and eliminate tumor cells while minimizing harm to healthy tissues.
Monoclonal Antibodies
Monoclonal antibodies are laboratory-made proteins designed to mimic the antibodies naturally produced by the immune system. These antibodies are engineered to precisely recognize and attach to specific targets, such as CLDN18.2, on the surface of cancer cells. Once bound, the antibody acts like a flag, signaling the patient’s own immune system to identify and destroy the marked cancer cells. This process can involve activating immune effector cells, such as natural killer (NK) cells, through antibody-dependent cellular cytotoxicity (ADCC), or triggering the complement system, which leads to complement-dependent cytotoxicity (CDC). Zolbetuximab is a prominent example of a CLDN18.2-targeting monoclonal antibody that has shown promise in clinical trials for gastric and gastroesophageal junction cancers.
Antibody-Drug Conjugates (ADCs)
Antibody-drug conjugates, or ADCs, can be thought of as “smart bombs” for cancer cells. These sophisticated therapies combine a monoclonal antibody, like those targeting CLDN18.2, with a potent chemotherapy drug. The antibody component specifically seeks out and binds to CLDN18.2 on the cancer cell surface. Once attached, the ADC is internalized by the cancer cell, delivering the chemotherapy drug directly inside. This targeted delivery mechanism allows for a higher concentration of the drug within the tumor cells, while minimizing systemic exposure and reducing damage to healthy cells throughout the body.
CAR-T Cell Therapy
Chimeric Antigen Receptor (CAR)-T cell therapy represents a “living drug” approach to cancer treatment. This therapy involves collecting a patient’s own immune cells, specifically T-cells, from their blood. These T-cells are then genetically engineered in a laboratory to express a specialized receptor, known as a CAR, on their surface. This CAR is designed to recognize and bind to specific proteins on cancer cells, such as CLDN18.2. Once engineered, these modified CAR-T cells are multiplied and re-infused back into the patient, where they actively seek out and destroy CLDN18.2-expressing cancer cells.
Identifying Cancers for Targeted Therapy
Before considering CLDN18.2-targeted therapies, it is important to determine if a patient’s tumor expresses this protein. Not all tumors of a specific type, even gastric or pancreatic cancers, will have the CLDN18.2 target present. Therefore, a diagnostic step is needed to identify eligible patients.
The process typically begins with obtaining a biopsy of the tumor tissue. A biopsy involves taking a small sample of the tumor, which is then sent to a laboratory for analysis. This tissue sample provides the necessary material for specialized testing.
The primary method used to detect CLDN18.2 expression is immunohistochemistry (IHC), a laboratory technique that uses specific antibodies designed to bind to the CLDN18.2 protein in the tissue sample. When these antibodies bind, they create a visible “stain” that pathologists can observe under a microscope. This staining reveals whether CLDN18.2 is present on the cancer cells and, importantly, at what level of intensity and on what percentage of cells it is expressed. For instance, CLDN18.2 positivity is often defined as at least moderate-to-strong membranous staining in 75% or more of viable tumor cells. This detailed assessment is a prerequisite for guiding the selection of CLDN18.2-targeted therapies.