Discovery, Function, and Therapeutic Targeting of Siglec-8

Abstract

Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate in inflammatory responses by releasing mediators that attract or activate other cells, contributing to the pathogenesis of allergic and non-allergic diseases. Since its discovery in 2000, initial in vitro studies have found that the engagement of Siglec-8 with a monoclonal antibody or with selective polyvalent sialoglycan ligands induced the cell death of eosinophils and inhibited mast cell degranulation. Anti-Siglec-8 antibody administration in vivo to humanized and transgenic mice selectively expressing Siglec-8 on mouse eosinophils and mast cells confirmed the in vitro findings, and identified additional anti-inflammatory effects. AK002 (lirentelimab) is a humanized non-fucosylated IgG1 antibody against Siglec-8 in clinical development for mast cell- and eosinophil-mediated diseases. AK002 administration has safely demonstrated the inhibition of mast cell activity and the depletion of eosinophils in several phase 1 and phase 2 trials. This article reviews the discovery and functions of Siglec-8, and strategies for its therapeutic targeting for the treatment of eosinophil- and mast cell-associated diseases.

Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

“…These receptors and/or their tissue and cellular ligands may identify novel targets for therapeutic modulation of eosinophil activation, survival and function. To this end, a humanized afucosylated antibody against Siglec 8, demonstrated to induce eosinophil death and inhibit mast cell degranulation, is in clinical development for eosinophil-mediated diseases [113][114][115].…”

“…As mentioned in Section 4.2.3 above, a non-fucosylated antibody targeting Siglec 8 (lirentelimab) has been shown to induce eosinophil cell death and inhibit mast cell degranulation. An in-depth review of Siglec 8 and its promise as a therapeutic target is included elsewhere in this journal issue [114]. Phase 2/3 studies of lirentelimab are currently underway in EGIDs (ENIGMA 2; NCT04322604 and KRYPTOS; NCT04322708).…”

Regulation of Eosinophilia in Asthma—New Therapeutic Approaches for Asthma Treatment

“…Sialic-acid-binding immunoglobulin-like lectin (Siglec)-8 is a cell-surface inhibitory receptor expressed selectively on human eosinophils (Figure 1) and mast cells, and it is under investigation as a therapeutic target for the treatment of allergic and inflammatory diseases [111][112][113]. The binding of a monoclonal antibody to Siglec-8 (lirentelimab/AK002) has been shown to induce death of cytokine-primed eosinophils via antibody-dependent cellular cytotoxicity (ADCC) [112].…”

The Crossroads of Glycoscience, Infection, and Immunology

“…When inhibitory Siglecs on activated immune cells encounter their native glycan ligands on target tissues, the immune cells apoptose or are otherwise inhibited, halting the ongoing immune event. Based on these findings, Siglecs are being targeted therapeutically as immune checkpoint inhibitors ( Youngblood et al, 2020 ).…”