Interleukin-3 receptor subunit alpha (CD123) and T-cell surface glycoprotein CD3 epsilon chain (CD3e) complex (CD123-CD3e)

The CD123-CD3e immune synapse interface is a therapeutic target complex formed by the interaction of bispecific antibodies or T-cell engagers with the Interleukin-3 receptor subunit alpha (CD123) and the T-cell surface glycoprotein CD3 epsilon chain (CD3e). CD123 is a type I transmembrane protein that serves as the primary binding subunit for interleukin-3 and is significantly overexpressed on leukemic blasts and stem cells in conditions such as acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) (UniProt P26951). CD3e is a critical component of the T-cell receptor (TCR) complex, essential for T-cell activation and signal transduction (UniProt P07766). By simultaneously binding to both proteins, bispecific agents like flotetuzumab and vibecotamab facilitate the formation of an artificial immune synapse, bringing cytotoxic T-cells into direct proximity with CD123-expressing tumor cells. This interaction triggers MHC-independent T-cell activation, leading to the secretion of perforins and granzymes that induce apoptosis in the target malignant cells (Uy et al., Blood, 2021). Clinical application of drugs targeting this interface is primarily focused on hematologic malignancies, with major safety considerations including cytokine release syndrome (CRS) and potential myelosuppression due to low-level CD123 expression on normal hematopoietic progenitors.

Other names

CD123 x CD3IL3RA-CD3E interfaceCD123-CD3 bispecific targetCD123-CD3 DART target

Bispecific T-cell redirection leading to the formation of an artificial immune synapse and subsequent T-cell mediated cytolysis of CD123-positive cells.