Sialic acid binding immunoglobulin-like lectin 3 (CD33) (CD33)

CD33 (sialic acid binding immunoglobulin-like lectin 3, abbreviated as CD33 or Siglec-3) is a transmembrane inhibitory receptor expressed predominantly on cells of the myeloid lineage, including monocytes, myeloid progenitors, macrophages, and dendritic cells, and to a lesser extent on some lymphoid subsets such as NK cells[1][2][3][4][5][7]. It is a member of the SIGLEC (sialic acid-binding immunoglobulin-like lectin) family, containing an IgV and an IgC2 domain extracellularly and two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) intracellularly. CD33 binds sialic acid–bearing glycans, acting as a self-associated molecular pattern recognition receptor that modulates immune activation and homeostasis, particularly by recruiting SHP-1 and SHP-2 phosphatases upon ligand engagement[1][3][5][10]. CD33 functions as an inhibitory checkpoint in innate and adaptive immunity; it is clinically relevant as a therapeutic target in acute myeloid leukemia (AML), where it is targeted by antibody–drug conjugates like gemtuzumab ozogamicin. Downregulation of CD33 is also under investigation for potential benefit in neurodegenerative diseases such as Alzheimer disease, where CD33 inhibition may enhance microglial clearance of pathological protein aggregates[3][4][9]. Safety challenges for CD33-targeted therapies include cytopenias due to ablation of normal myeloid cells and potential immunosuppression[4].

Other names

Siglec-3SIGLEC3gp67p67sialic acid binding Ig-like lectin 3

Antibody–drug conjugates: Target CD33-positive cells for internalization and toxin-induced cell death (e.g., gemtuzumab ozogamicin) Immune modulation: Blockade or engagement of CD33 can alter phagocytosis, cytokine production, and cytotoxicity by myeloid and NK cells Immunoinhibition: Drugs may interfere with CD33’s ITIM-mediated recruitment of SHP-1/2 phosphatases, altering downstream inhibitory signaling