CD123 x CD3

Class

Bispecific T-cell engaging antibody (ADAPTIR platform)

Pathway

T-cell redirected cytotoxicity against CD123-positive blasts

CD123 is the alpha subunit of the interleukin-3 receptor, a signaling protein expressed at markedly elevated density on blasts in acute myeloid leukemia and related myeloid malignancies, while present at lower levels on a subset of normal blood-forming and immune cells. A CD123 x CD3 bispecific antibody is engineered with two binding arms: one recognizes CD123 on the malignant cell, the other recognizes CD3, a component of the T-cell receptor complex on cytotoxic T lymphocytes. By physically bridging these two cell types, the molecule forms an artificial immune synapse that activates T cells independent of their native antigen specificity, prompting them to kill the CD123-bearing target cell. This strategy, called T-cell redirected cytotoxicity, is designed to harness a patient's own cytotoxic T-cell machinery against leukemic cells that might otherwise evade immune surveillance, since it does not depend on prior antigen presentation or a matched T-cell receptor repertoire. CD123 was chosen as the target antigen because its expression is relatively enriched on myeloid leukemic cells compared with the broader blood-forming compartment, offering a therapeutic window. This mechanism is broadly relevant to hematologic malignancies, particularly acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm, conditions in which residual leukemic stem and progenitor cells often persist despite conventional treatment.