Anti-CD33 Monoclonal Antibody (Vadastuximab)

CD33, also known as Siglec-3, is a 67 kDa type-I transmembrane sialic-acid-binding immunoglobulin-like lectin composed of an N-terminal V-set Ig domain that mediates glycan recognition, a membrane-proximal C2-set Ig domain, and a cytoplasmic tail harboring two immunoreceptor tyrosine-based inhibitory motifs (ITIMs); upon ligation by α2,3- or α2,6-linked sialylated glycoproteins or the complement component C1q, Src-family kinases phosphorylate these ITIMs, recruiting the SH2-domain-containing phosphatases SHP-1 and SHP-2 that dephosphorylate downstream signaling molecules, thereby suppressing calcium flux, PI3K activity, and activation of myeloid cells including monocytes, macrophages, dendritic cells, microglia, and myeloid-derived suppressor cells, while also modulating NK-cell cytotoxicity and cytokine production; CD33 is highly expressed on committed myeloid progenitors and over-expressed on >90 % of acute myeloid leukemias, making it the target of the antibody–drug conjugate gemtuzumab ozogamicin, and alternative splicing generates a shorter isoform lacking the ligand-binding V domain that can still dampen immune responses; genetically, the rs3865444(C) allele that reduces CD33 surface expression is protective against late-onset Alzheimer’s disease because lower microglial CD33 lessens inhibition of Aβ phagocytosis, implicating the receptor in neurodegeneration as well as in infection, autoimmunity, and cancer immune evasion.