Zolbetuximab is a new class of cancer medication, a type of monoclonal antibody. This drug targets specific features on tumor cells. Its primary role is as a targeted therapy, identifying and destroying cancer cells while minimizing harm to healthy tissues. Zolbetuximab focuses on unique biological markers found on malignant cells.
The Unique Target: CLDN18.2
CLDN18.2, or Claudin 18.2, is a protein that serves as a component of tight junctions in healthy cells. These tight junctions are structures that help seal the spaces between cells, maintaining the integrity and barrier function of epithelial layers, such as those lining the stomach. In normal gastric tissue, CLDN18.2 is typically hidden within these tight junctions, making it largely inaccessible.
However, in certain cancers, particularly those originating in the stomach and gastroesophageal junction, CLDN18.2 undergoes a transformation. The protein becomes exposed on the surface of cancer cells due to disruptions in cell polarity and structural changes within the tumor. This exposure makes CLDN18.2 a distinct and accessible target for therapeutic intervention. Its limited presence on healthy tissues, combined with its overexpression and surface exposure on cancer cells, makes it an attractive target for selective tumor therapies.
Unveiling Zolbetuximab’s Action
Zolbetuximab is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody engineered to specifically bind to CLDN18.2 on cancer cells. This binding initiates immune responses to eradicate malignant cells. The antibody’s Fc region becomes available for recognition by immune effector cells once zolbetuximab is bound to CLDN18.2.
One primary mechanism of action is antibody-dependent cell-mediated cytotoxicity (ADCC). When zolbetuximab binds to CLDN18.2 on a cancer cell, immune cells such as natural killer (NK) cells recognize the antibody’s Fc region. This recognition activates the NK cells, prompting them to release cytotoxic molecules that induce programmed cell death, or apoptosis, in the targeted cancer cells.
Zolbetuximab also triggers complement-dependent cytotoxicity (CDC). Upon binding to CLDN18.2 on tumor cells, zolbetuximab activates the complement system, part of the innate immune response. This activation leads to the formation of the membrane attack complex (MAC) on the surface of the targeted cancer cells. The MAC creates pores in the cell membrane, disrupting its integrity and leading to cell lysis. These dual mechanisms, ADCC and CDC, work together to destroy CLDN18.2-positive cancer cells.
Where Zolbetuximab is Applied
Zolbetuximab is developed for certain advanced cancers where CLDN18.2 is present. It is approved for patients with locally advanced unresectable or metastatic HER2-negative gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2-positive. This means the drug treats cancers that have spread or cannot be surgically removed, and express this protein.
CLDN18.2 is present in approximately 50% to 80% of stomach malignancies, making it a relevant target. Zolbetuximab offers a targeted treatment option for these patients. It is typically administered with chemotherapy to enhance treatment efficacy.