Anti-Claudin-18 Isoform2-Anti-4-1BB Bispecific Antibody (Givastomig)

Givastomig is a bispecific antibody (BsAb) that targets Claudin-18 Isoform2 (CLDN18.2) and 4-1BB (CD137 or TNFRSF9), and has a single Fc-domain mutation (asparagine to alanine), which eleminates Fc-effector function. It binds to the surface of activated T and NK cells. It is being investigated for the treatment of gastric cancer. Claudins are integral membrane proteins and components of tight junction strands which serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets. The claudin-18 gene has two splice variants: claudin-18.1, which is found primarily in the lung, and claudin-18.2, which is expressed exclusively in the stomach. Claudin-18.2 is highly expressed in gastric and pancreatic adenocarcinoma and may be involved in tumor development and progression. Due to the morphological changes and epithelial-mesenchymal transition occurring upon cancer progression, the extracellular loops of claudin 18.2 become exposed and available for antibody binding. These biological characteristics suggest that it is an ideal target for therapy and have led to the further development of monoclonal antibodies against claudin 18.2, such as Zolbetuximab. Givastomig is a bispecific antibody that targets claudin 18.2 and 4-1BB and is being considered for the treatment of gastric cancer.