The body’s cells are organized into tissues and organs, often separated by specialized structures called tight junctions. These junctions act as a selective barrier, controlling what passes between cells and maintaining the cells’ proper arrangement. A family of proteins known as claudins are the primary components of these tight junctions.
Claudins are small proteins with four segments that span the cell membrane, interacting with neighboring claudins to form a seal. They also connect to the cell’s internal scaffolding and signaling proteins. Claudin 18 is a specific member of this protein family, identified for its distinct tissue-specific expression patterns.
The Role of Claudin 18 in the Body
Claudin 18 plays a specific role in maintaining the integrity of certain bodily barriers. It is primarily found in the stomach lining, where it helps form a tight seal between epithelial cells. This protein regulates the passage of substances between cells, particularly restricting the movement of hydrogen and sodium ions to protect the stomach from its own acidic environment.
Claudin 18 has two main forms, or isoforms, known as Claudin 18.1 and Claudin 18.2, which differ slightly in their amino acid sequences. Claudin 18.1 is predominantly found in the alveolar epithelial cells of the lung, where it contributes to the epithelial barrier function and may play a role in lung regeneration. Claudin 18.2, in contrast, is almost exclusively expressed in the differentiated cells of the stomach lining. This isoform is normally hidden within the tight junctions, making it inaccessible to external molecules.
Claudin 18 in Disease Development
The normal function of Claudin 18 can be significantly altered in various disease states, particularly in cancer. During the malignant transformation of these cells, the tight junctions can become disorganized, leading to the exposure of Claudin 18.2 on the surface of cancer cells, making it a potential target for treatments.
Claudin 18.2 is aberrantly expressed or re-expressed in several types of cancer, most notably gastric (stomach) cancer, where it is found in a significant proportion of tumors. Its expression can also be observed in other malignancies, including pancreatic, esophageal, ovarian, and lung cancers. The level of Claudin 18.2 expression in tumors can vary, but its presence on the cell surface in these cancers makes it an attractive target for specific therapies. In gastric cancer, Claudin 18.2 expression is often maintained even in metastatic lesions, providing a consistent target for systemic treatments.
Targeting Claudin 18 in Treatment
The unique expression pattern of Claudin 18.2 makes it a valuable target for cancer therapies. This specificity allows for the development of treatments that can selectively attack cancer cells. Targeted therapies like monoclonal antibodies are designed to recognize and bind to specific molecules on cancer cells.
Zolbetuximab is a monoclonal antibody that specifically targets Claudin 18.2. It works by binding to the Claudin 18.2 protein on the surface of cancer cells, which then triggers the body’s immune system to destroy these cells. This destruction occurs through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Zolbetuximab has demonstrated promising results in clinical trials for advanced gastric and gastroesophageal junction adenocarcinoma, improving progression-free survival and overall survival when combined with chemotherapy. It received regulatory approval in Japan, the UK, and the US FDA in 2024 for the treatment of CLDN18.2-positive gastric and gastroesophageal junction cancers.
Future Directions and Research
Ongoing research continues to explore Claudin 18.2 in cancer management. Scientists are investigating Claudin 18.2 as a diagnostic biomarker, which could help in identifying patients whose tumors express this protein, thereby guiding treatment decisions. This includes exploring its detection in liquid biopsies, which are less invasive ways to monitor cancer.
The potential for combining Claudin 18.2-targeting agents with other cancer treatments, such as chemotherapy or immunotherapy, is also an area of research. These combination therapies aim to improve patient outcomes. Beyond Claudin 18.2, broader research into other claudin family members and tight junction biology continues, potentially revealing new therapeutic avenues.