Multi-Mechanistic Approaches to Disarming IgE-Mediated Allergic Diseases 2304105

Abstract

Abstract Introduction Pathogenic IgE production contributes to a wide range of allergic and atopic diseases. Binding of allergen-specific IgE to its high-affinity IgE receptor FcεRI on basophils and mast cells results in allergen-mediated cross-linking of FcεRI-bound IgE triggering the release of inflammatory mediators causing allergic reactions. We briefly highlight here Seismic’s multiple approaches to rapidly disarm the allergic effector cells. These include (i) cleaving and eliminating circulating IgE, (ii) dissociating IgE from effector cells and down-modulating effector function, and (iii) sweeping IgE from circulation for clearance. Here we will focus on the discovery and design of our IgE dissociator that rapidly dissociates IgE from FcεRI on effector cell surfaces and preventing cell activation, as well as preventing binding of free IgE to FcεRI and FcεRII. Methods IgE dissociators, discovered from an immunization campaign, were screened by surface plasmon resonance and in primary human cell-based assays using flow cytometry for their ability to dissociate IgE from FcεRI. Confirmatory basophil activation assays were performed on human whole blood. Pharmacokinetics (PK), pharmacodynamics (PD) and in vivo efficacy were tested using relevant preclinical models. Results The IgE dissociator rapidly dissociates IgE from the high affinity receptor FcεRI on basophil and mast cell surfaces without triggering degranulation, and shows superior IgE dissociation and FcεRI down modulation compared to standard of care in preclinical models. It exhibits multi-pharmacology by preventing free IgE binding to FcεRI and FcεRII. It demonstrates favorable PK, PD and efficacy in murine model of acute anaphylaxis. Conclusion Our IgE dissociator molecules address multiple aspects of IgE pathology by rapidly removing FcεRI-bound IgE and neutralizing free IgE without triggering effector-cell activation, providing a unique and potentially more effective approach to treat IgE-driven allergic and atopic diseases. Funding Source n/a Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)