Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions

Abstract

Siglecs (sialic acid immunoglobulin-like lectins) are members of the immunoglobulin gene family that contain sialoside binding N-terminal domains. They are cell surface proteins found predominantly on cells of the immune system. Among them, Siglec-8 is uniquely expressed by human eosinophils and mast cells, as well as basophils. Engaging this structure with antibodies or glycan ligands results in apoptosis in human eosinophils and inhibition of release of preformed and newly generated mediators from human mast cells without affecting their survival. Pro-apoptotic effects are also seen when its closest functional paralog, Siglec-F, on mouse eosinophils is similarly engaged in vitro, and beneficial effects are observed after administration of Siglec-F antibody using models of eosinophilic pulmonary and gastrointestinal inflammation in vivo. Siglec-8 targeting may thus provide a means to specifically inhibit or deplete these cell types. Cell-directed therapies are increasingly sought after by the pharmaceutical industry for their potential to reduce side effects and increase safety. The challenge is to identify suitable targets on the cell type of interest, and selectively deliver a therapeutic agent. By targeting Siglec-8, monoclonal antibodies and glycan ligand-conjugated nanoparticles may be ideally suited for treatment of eosinophil and mast cell-related diseases, such as asthma, chronic rhinosinusitis, chronic urticaria, hypereosinophilic syndromes, mast cell and eosinophil malignancies and eosinophilic gastrointestinal disorders.

Structural basis for sulfation-dependent self-glycan recognition by the human immune-inhibitory receptor Siglec-8

“…Indeed, Siglec-8 gene polymorphisms were identified to correlate with increased asthma risk (21), albeit the detailed molecular pathways linking Siglec-8 to disease have yet to be clarified. On account of its potent eosinophil proapoptotic and mast cell-inhibitory activities, combined with its selective expression on these key inflammatory effector cells, Siglec-8 is considered a promising target for novel antiinflammatory, proresolving treatment strategies for asthma and other disease conditions in which inappropriate and/or prolonged inflammatory responses of these cell types contributes to pathology (20,(22)(23)(24)(25).…”

Improving the diagnosis of eosinophilic asthma

“…For example, Siglec-8 correlates with blood eosinophils and has been identified as a marker for HESs [91]. This protein might even become a target for new therapies as this protein plays a role in apoptosis of eosinophils [92]. Whether this surface marker is useful as biomarker or therapeutic target in eosinophilic asthma needs to be further explored.…”

Inhaled Corticosteroids Increase Siglec-5/14 Expression in Sputum Cells of COPD Patients

“…These receptors recognize and bind to α2-3-, α2-6-and α2-8-linked sialic acid residues on the cell surface and trigger, depending on the structure of the intracellular domain, opposing signaling cascades resulting in cellular activation or inhibition (Varki and Gagneux 2012;Angata et al 2006). Recent studies suggest that several Siglecs, such as Siglec-8 and Siglec-14 participate in the inflammatory mechanisms in asthma and COPD and may serve as an important therapeutic target (Ilmarinen and Kankaanranta 2014;Angata et al 2013;Mroz et al 2013;Kiwamoto et al 2012). In the present study, we quantified Siglec-5/14 expression in induced sputum cells of COPD patients treated with a long-acting beta2-agonist (LABA) alone, in combination with a long-acting antimuscarinic agent (LAMA) or inhaled corticosteroid (ICS), and finally in a triple combination of LABA/LAMA/ICS.…”