title: 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.
authors: Department of Medicine, Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
authors: Takumi
authors: T
authors: Kiwamoto
authors: Norihito
authors: N
authors: Kawasaki
authors: James C
authors: JC
authors: Paulson
authors: Bruce S
authors: BS
authors: Bochner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD / Q000502:physiology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology; D015214:Antigens, Differentiation, Myelomonocytic / Q000187:drug effects / Q000502:physiology*; D004802:Eosinophilia / Q000188:drug therapy / Q000503:physiopathology; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D006801:Humans; D037102:Lectins / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D008415:Mastocytosis / Q000188:drug therapy / Q000503:physiopathology; D058990:Molecular Targeted Therapy / Q000379:methods*; D053758:Nanoparticles / Q000627:therapeutic use; D011134:Polysaccharides / Q000494:pharmacology / Q000627:therapeutic use; D063265:Sialic Acid Binding Immunoglobulin-like Lectins
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D015214:Antigens, Differentiation, Myelomonocytic; D037102:Lectins; D011134:Polysaccharides; C403967:SIGLEC8 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C443130:Siglecf protein, mouse