SIGLEC8 (sialic acid-binding immunoglobulin-type lectin 8) is a cell surface receptor predominantly expressed on eosinophils, mast cells, and a subset of basophils. As a member of the SIGLEC family, it recognizes sialylated glycans and plays a role in modulating immune cell activity. Its cytoplasmic domain contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs), enabling it to transmit inhibitory signals that regulate cell activation, survival, and effector functions. In eosinophils, SIGLEC8 engagement promotes apoptosis and suppresses inflammatory mediator release, while in mast cells, it inhibits IgE-mediated degranulation.
SIGLEC8 has emerged as a therapeutic target for eosinophil- and mast cell-driven diseases, such as severe asthma, chronic urticaria, eosinophilic gastrointestinal disorders, and mast cell activation syndromes. Antibodies targeting SIGLEC8 are designed to exploit its inhibitory signaling or induce targeted cell depletion. For example, agonistic antibodies that crosslink SIGLEC8 can trigger eosinophil apoptosis or suppress mast cell hyperactivity. Conversely, antibody-dependent cellular cytotoxicity (ADCC)-enhanced antibodies may directly eliminate pathogenic cells.
Preclinical studies demonstrate that SIGLEC8-targeting antibodies reduce tissue eosinophilia and mast cell-mediated inflammation. Several candidates are in clinical development, offering potential precision therapies for diseases with limited treatment options. By selectively targeting pathogenic cells while sparing broader immune functions, SIGLEC8 antibodies aim to achieve efficacy with reduced systemic toxicity compared to conventional immunosuppressants.