Interleukin-3 receptor subunit alpha (CD123) (CD123)

Interleukin-3 receptor subunit alpha (CD123) is a type I transmembrane glycoprotein that functions as the primary binding subunit of the high-affinity interleukin-3 (IL-3) receptor complex [1, 10, 12]. In normal physiology, CD123 is expressed at low levels on hematopoietic progenitor cells and mediates IL-3-induced signaling for the proliferation, survival, and differentiation of various hematopoietic lineages [4, 8, 10]. However, CD123 is significantly overexpressed in several hematologic malignancies, most notably in approximately 80% of patients with acute myeloid leukemia (AML), where it is found on both bulk leukemic blasts and leukemic stem cells (LSCs) [1, 2, 5, 8]. This overexpression, particularly on LSCs compared to normal hematopoietic stem cells, makes CD123 a high-priority therapeutic target for eradicating the reservoir of cells responsible for disease relapse and chemoresistance [1, 3, 7, 10]. Therapeutic strategies targeting CD123 include the approved immunotoxin tagraxofusp, as well as investigational antibody-drug conjugates, bispecific T-cell engagers, and CAR-T cell therapies [1, 2, 3, 6]. Clinical challenges include managing severe toxicities such as capillary leak syndrome and cytokine release syndrome, as well as addressing the potential for on-target, off-tumor effects on normal cells like plasmacytoid dendritic cells and endothelial cells [2, 6, 11]. CD123 expression also serves as a critical biomarker for minimal residual disease (MRD) monitoring and is often associated with high-risk genetic markers like FLT3-ITD and NPM1 mutations [1, 3, 7, 13, 14]. Ongoing research focuses on optimizing the therapeutic window and combining CD123-targeted agents with standard-of-care therapies to improve outcomes in refractory AML [5, 6, 15].

Other names

IL3RAIL-3R-alphahIL-3RaInterleukin-3 receptor alpha chain

Drugs targeting CD123 utilize several mechanisms, including targeted delivery of cytotoxic payloads (immunotoxins and antibody-drug conjugates), recruitment of T-cells via bispecific antibodies (BiTEs/DARTs), and direct cellular cytotoxicity through CAR-T cell therapy or antibody-dependent cellular cytotoxicity (ADCC) [1, 2, 3, 4, 6, 11].