R01 AI072265, NIH/NIAID - Bochner (PI)
Studies in this grant will explore whether Siglec-8, a molecule selectively expressed by eosinophils and mast cells, can be targeted for both diagnostic and therapeutic purposes in allergic, gastrointestinal and malignant diseases.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. The goal of these efforts 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 involve use of nanoparticles for imaging of eosinophilic inflammation, 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, and use of Siglec-8/-F targeting liposomes carrying chemotherapies or our Siglec-8 mAb to treat malignant diseases involving eosinophils and mast cells.