Discovery, characterization and preclinical evaluation a novel engineered Fc-fused IgE cleaving enzyme for the treatment of IgE-mediated diseases 2253523

Abstract

Abstract Introduction A novel Fc-fused bacterial-derived IgE cleaving protease was identified and engineered using our proprietary IMPACT platform. Through our machine learning enabled platform, the IgE protease was engineered to reduce immunogenicity and improved manufacturability while maintaining potency. It selectively cleaves human and non-human primate IgE, eliminating IgE from circulation and subsequently, from the cell-surface providing a novel therapeutic opportunity to treat IgE-mediated inflammation. Methods The IgE protease was characterized in vitro to determine its ability to cleave soluble and membrane-bound IgE using plate-based MSD assays and cell-based FACS assays. Reduced immunogenicity was confirmed in T cell proliferation assays Results Pharmacokinetics, pharmacodynamics and in vivo efficacy were tested using relevant preclinical models. The engineered IgE protease shows extended pharmacokinetics and efficacy in humanized mouse models of local and systemic acute anaphylaxis (PCA and PSA). In a rat allergic asthma model, it shows reduction of soluble IgE levels and lower eosinophils counts in bronchoalveolar fluid. Additionally, we observe a clear PK/PD relationship and reduction of serum IgE in non-human primates Conclusion Given its ability to simultaneously address multiple aspects of IgE pathogenesis and its efficacy in preclinical models of anaphylaxis, the engineered Fc-protease offers a new approach to targeted therapy for allergic and atopic diseases where IgE is a key driver Funding Source n/a Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)