(Seismic) Discovery and characterization of a novel engineered Fc-fused IgE cleaving enzyme for treatment of IgE mediated diseases

Abstract

Rationale: The dysregulation of humoral immune mechanisms results in pathogenic IgE production that contributes to a range of allergic and atopic diseases such as food allergies, acute anaphylaxis, allergic asthma, allergic rhinitis and chronic spontaneous urticaria. We present a novel Fc-fused bacterially-derived IgE protease that was engineered using a proprietary machine learning enabled platform to reduce immunogenicity and improve manufacturability while maintaining potency. The protease selectively cleaves IgE, eliminating it from circulation, the cell-surface and immune-complexes, and provides a novel therapeutic opportunity to treat IgE-mediated inflammation.

Methods: The engineered Fc-fused IgE protease was identified using our proprietary IMPACT platform and was characterized in vitro to determine its ability to cleave IgE using MSD and flow cytometry-based cleavage assays. Immunogenicity was assessed using T cell proliferation assays. Pharmacokinetics, pharmacodynamics and in vivo efficacy were tested using relevant preclinical models.Results: The engineered Fc-protease selectively cleaves IgE, while improving stability and demonstrating low immunogenicity. It cleaves soluble IgE in human plasma with high potency, IgE+ BCR and IgE bound to CD23/FcεRII in B cell lines. Remarkably, this protease shows extended pharmacokinetics and efficacy in preclinical models of local and systemic acute anaphylaxis, suggesting an impact on IgE-mediated effector functions.

Conclusions: 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.