Cell surface glycoprotein A33 (GPA33)

Cell surface glycoprotein A33 (GPA33) is a 43 kDa transmembrane protein belonging to the immunoglobulin superfamily, characterized by its highly restricted expression in the intestinal epithelium [1, 7]. It is notably overexpressed in over 95% of primary and metastatic colorectal cancers and approximately 50% of gastric cancers, making it a highly specific biomarker and therapeutic target for gastrointestinal malignancies [1, 2, 10]. Biologically, GPA33 is involved in cell-cell adhesion and the maintenance of the intestinal mucosal barrier, and it also serves as a marker for stable thymus-derived regulatory T cells [5, 17]. In the context of drug development, GPA33 has been targeted using various modalities, including monoclonal antibodies, bispecific T-cell engagers, and radioimmunotherapy agents, which leverage its persistent surface expression and internalization properties [6, 11, 15]. While its presence in normal intestinal tissue poses a risk for on-target, off-tumor toxicity, clinical trials have demonstrated significant tumor-selective accumulation [11, 14]. Current research also explores its use in CAR-T and CAR-macrophage therapies to overcome the immunosuppressive tumor microenvironment in solid tumors [2, 3].

Other names

A33Glycoprotein A33Cell surface A33 antigenTransmembrane glycoprotein A33

The primary mechanisms of action for drugs targeting GPA33 include antibody-dependent cellular cytotoxicity (ADCC), T-cell redirection via bispecific antibodies, and the delivery of ionizing radiation through radioimmunotherapy (RIT) or pretargeted radioimmunotherapy (PRIT) [1, 6, 10, 15]. Additionally, chimeric antigen receptor (CAR) technologies, such as CAR-T and CAR-macrophages, are being developed to induce direct antigen-dependent lysis and phagocytosis of tumor cells [2, 3].