Sialic acid-binding Ig-like lectin 3 and Interleukin-3 receptor subunit alpha (CD33 and CD123) (CD33 and CD123)

CD33 (Sialic acid-binding Ig-like lectin 3) and CD123 (Interleukin-3 receptor subunit alpha) are cell surface receptors that are highly co-expressed on the blasts and leukemic stem cells (LSCs) of the majority of patients with acute myeloid leukemia (AML) [1, 6, 17]. CD33 is a member of the Siglec family that typically functions as an inhibitory receptor through its immunoreceptor tyrosine-based inhibitory motifs (ITIMs), modulating immune cell activation and phagocytosis [2, 4, 7]. CD123 is the alpha subunit of the high-affinity interleukin-3 receptor, which plays a critical role in the proliferation, survival, and differentiation of hematopoietic cells [1, 11, 12]. Dual targeting of these antigens is an emerging therapeutic strategy designed to increase the precision of anti-leukemic treatments and prevent disease relapse caused by antigen escape or clonal heterogeneity [3, 13, 18]. Current therapeutic approaches include bispecific antibodies, T-cell engagers, and CAR-T cells that aim to selectively eliminate malignant cells while minimizing damage to healthy hematopoietic stem cells and other tissues [6, 10, 20]. Despite their promise, these therapies face significant challenges, including potential myelosuppression and capillary leak syndrome due to the expression of these targets on normal myeloid progenitors and endothelial cells [10, 14, 15].

Other names

SIGLEC3Siglec-3p67gp67IL3RAIL-3R alphahIL-3RaInterleukin-3 receptor alpha chain

Drugs targeting CD33 and CD123 utilize several mechanisms: antibody-drug conjugates (ADCs) deliver cytotoxic payloads directly to malignant cells; bispecific T-cell engagers (BiTEs) or Nanobody-based engagers recruit and activate T-cells to kill target cells; and chimeric antigen receptor (CAR) T-cells are engineered to recognize and eliminate cells expressing one or both antigens. Additionally, some agents block IL-3 mediated signaling or modulate inhibitory immune pathways.