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.

Fig. 1

Nomenclature and key structural characteristics of human siglecs. Although 15 are shown, Siglec-13 is present in nonhuman primates but not in man. V structures indicate the arginine-containing V-set domains with lectin activity; these are followed by C2-type Ig repeat domains. U-shaped structures for Siglec-XII indicate the mutated V-set domains missing arginine that have lost their lectin activity. Also shown is DAP12, illustrated as a shorter transmembrane structure co-associating with Siglec-13, Siglec-14, and Siglec-15. See key for symbols representing cytoplasmic signaling motifs. Reproduced from von Gunten and Bochner (2008), with permission.

Fig. 2

Nomenclature and key structural characteristics of mouse siglecs. V structures indicate the arginine-containing V-set domains with lectin activity; these are followed by C2-type Ig repeat domains. Also shown is DAP12, illustrated as a shorter transmembrane structure co-associating with Siglec-15 and Siglec-H. Whether Siglec-H, shown as having an arginine-containing V-set domains with lectin activity, can bind sialic acid ligands remains controversial but there is no human counterpart. Note that Siglecs-1–4 are conserved with humans, as is Siglec-15 (compare to Fig. 1). While not true orthologs, the closest functional paralog of Siglec-E is Siglec-9, while Siglec-F resembles Siglec-8 and Siglec-G resembles Siglec-10. Reproduced from von Gunten and Bochner (2008), with permission.

Fig. 3

CD22 ligand decorated cargo is released in endosomes and accumulates in the cell, while anti-CD22 antibody recycles to the cell surface. Illustrated is the fate of an anti-NP-IgM (‘the cargo’) targeted to CD22 on B cells using a heterobifunctional ligand comprising the antigen, NP, coupled to a high affinity ligand of CD22. Following ligand driven assembly of the anti-NP IgM:CD22 complex on the surface of the cell, endocytosis results in release of the anti-NP IgM in the acidic endosomal compartments. CD22 then goes back to the cell surface to capture another load of cargo, resulting in the accumulation of the glycan-based cargo (anti-NP IgM) inside the cell. In contrast, an anti-CD22 antibody (clone HIB22) is not released from CD22 in the endosomes, resulting in the complex of CD22 and the anti-CD22 antibody recycles between the cell surface and the endosomes with no accumulation of the antibody. By permission of Mary O’Reilly.