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.
Highlights
Siglecs are single-pass cell surface receptors that contain sialic acid-binding N-terminal V-set domains [1,2]. These receptors are predominately found on immune cells and most have immunoreceptor tyrosine-based motifs (ITIMs) that are involved in inhibitory cell signaling
Siglec-8 was discovered more than 20 years ago in a cDNA library generated from a subject with hypereosinophilic syndrome (HES) [9,10]
In addition to IL-33, Siglec-8 monoclonal antibodies (mAbs) treatment inhibited Substance P-induced mast cell activation, neutrophil infiltration, and cytokine production in Siglec-8 transgenic mice [63]. These data suggest that Siglec-8 mAb administration suppresses allergic and nonallergic inflammation mediated by mast cells or eosinophils, and that mast cells regulate the recruitment of immune cells, including neutrophils
Summary
Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that contain sialic acid-binding N-terminal V-set domains [1,2]. These receptors are predominately found on immune cells and most have immunoreceptor tyrosine-based motifs (ITIMs) that are involved in inhibitory cell signaling. The Siglec family of cell surface receptors have emerged as attractive therapeutic targets due to their restricted expression profile on immune cells and their immunomodulatory activities [3,4,5,6]. Our knowledge of the expression and function of Siglec-8 on mast cells and eosinophils has greatly expanded, as has our understanding of targeting Siglec-8 with monoclonal antibodies (mAbs) for potential therapeutic benefit. Function, and the potential for therapeutic targeting of Siglec-8 with mAbs
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