Sialic acid-binding immunoglobulin-type lectin (Siglec) receptor (Siglec)

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of cell-surface receptors primarily expressed on immune cells that recognize sialic acid-containing glycans (UniProt, 2023). They are classified as I-type lectins and belong to the immunoglobulin superfamily, featuring an N-terminal V-set domain responsible for ligand binding (PubMed, PMID: 24388214). Most Siglecs, such as CD22 (Siglec-2) and CD33 (Siglec-3), possess immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit phosphatases to suppress immune cell activation, thereby maintaining self-tolerance (Nature Reviews Immunology, 2014). In oncology, tumors often exploit this pathway by overexpressing sialic acids to engage inhibitory Siglecs, facilitating immune evasion (Cell, 2019). Therapeutic strategies include using Siglecs as targets for antibody-drug conjugates (ADCs) like Gemtuzumab ozogamicin or as immune checkpoints to enhance anti-tumor immunity (Journal of Hematology & Oncology, 2020). Additionally, Siglecs are implicated in neurodegenerative diseases, such as Alzheimer's, where Siglec-3/CD33 regulates microglial clearance of amyloid-beta (Neuron, 2013). Beyond cancer and neurodegeneration, they play roles in inflammatory and autoimmune disorders by modulating leukocyte activity (PubMed, PMID: 31515460). The diversity of the Siglec family allows for highly specific therapeutic targeting depending on the cell type and disease context.

Other names

Sialic acid-binding Ig-like lectinI-type lectinSIGLEC familyCD33-related Siglecs

Siglecs are targeted via several modalities: antibody-drug conjugates (ADCs) deliver cytotoxic agents to specific cell populations (e.g., CD33 in AML, CD22 in ALL); monoclonal antibodies act as checkpoint inhibitors by blocking the interaction between inhibitory Siglecs and their sialic acid ligands on tumor cells; and some approaches involve glycan-based ligands to modulate receptor activity (PubMed, PMID: 32636235; Nature Reviews Drug Discovery, 2021).