In anaphylaxis, asthma and other forms of acute and chronic allergic diseases, eosinophils and mast cells, through release of preformed and newly generated mediators, granule proteins, and cytokines, are felt to be key effector cells. For allergic diseases, drugs that inhibit mast cell degranulation, reduce eosinophil numbers, or counteract their released mediators are useful therapies, but all remain incompletely effective. Eosinophils and mast cells are implicated in other chronic diseases including eosinophilic esophagitis. Systemic Mastocytosis, a malignant disease, presents with varying prognoses depending on the extent of involvement, but Aggressive Systemic Mastocytosis and Mast Cell Leukemia are always fatal due to the lack of effective treatments. For eosinophil-related malignancies, the revised 2008 WHO classification recognizes both molecularly defined and undefined myeloid disorders, and there remains an unmet need for treatment of unexplained eosinophilia and """"""""chronic eosinophilic leukemia, not otherwise specified"""""""". Siglecs (sialic acid-binding, immunoglobulin-like lectins) are cell surface proteins found predominantly on leukocytes. Siglec-8 was discovered by us about a decade ago and is selectively expressed on eosinophils and mast cells. Its closest functional paralog in the mouse is Siglec-F, which is also selectively expressed by eosinophils but unfortunately not on mast cells. Both Siglec-8 and Siglec-F preferentially and uniquely recognize the glycan 6'-sulfo-sialyl Lewis X (6'-sulfo-sLeX) and its non-fucosylated form. Engagement of Siglec- 8/-F with antibodies (Abs) and/or artificial ligands causes eosinophil death. Administration of Siglec-F Abs in mouse models of chronic allergic asthma and eosinophilia normalizes eosinophilic inflammatory responses and abrogates lung remodeling. This application is a competitive renewal of R01 AI72265 entitled """"""""Targeting Siglec-8/Siglec-F to Reduce Allergic Responses in vitro and in vivo"""""""", funded from 07/01/07 with an ARRA supplement from 07/01/10-06/30/11. The overarching goals were to explore ligands for Siglec-8/-F, their functions, and the mechanisms by which they regulate eosinophilic and allergic responses. Since 2007, we have published 22 papers related to this award and have received six patents related to Siglec-8. The goal of the present application is to employ monoclonal antibodies (mAbs) and glycan ligands for Siglec-8 in highly translational, preclinical in vitro and murine studies (including Siglec-8 transgenics) to define their utility as therapeutic targets. Innovations include liposomal targeting to reduce systemic toxicity of drugs by selectively targeting Siglec-8/-F bearing cells, thus reducing total dose of drug delivered. Approaches proposed involve use of nanoparticles for imaging of eosinophilic inflammation (Aim 1), liposomal delivery of inhibitory drugs selectively to eosinophils or mast cells by targeting Siglec-8/-F and its ligands to treat allergic and inflammatory diseases involving these cells (Aim 2), and use of Siglec-8/-F targeting liposomes carrying chemotherapies or our Siglec-8 mAb to treat malignant diseases involving eosinophils and mast cells (Aim 3).
Allergic diseases and eosinophilic gastrointestinal disorders are not well controlled in a substantial number of patients, resulting in significant morbidity and cost. Prior studies have implicated two particular cell types, eosinophils and mast cells, in the pathogenesis of these disorders, and cancers involving these cells can be fatal. Studies in this grant application will explore whether Siglec-8, a molecule selectively expressed by these two cells, can be targeted for both diagnostic and therapeutic purposes.
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