Accelerated dissociation of IgE-FcεRI complexes by disruptive inhibitors actively desensitizes allergic effector cells

Abstract

Background The remarkably stable interaction of immunoglobulin E (IgE) with its high-affinity receptor FcεRI on basophils and mast cells is critical for the induction of allergic hypersensitivity reactions. Due to the exceptionally slow dissociation rate of IgE:FcεRI complexes such allergic effector cells permanently display allergen-specific IgE on their surface and immediately respond to allergen challenge by releasing inflammatory mediators. We have recently described a novel macromolecular inhibitor that actively promotes the dissociation of IgE from FcεRI through a molecular mechanism termed facilitated dissociation. Objective Here, we assessed the therapeutic potential of this non-immunoglobulin based IgE inhibitor DARPin E2_79 as well as a novel engineered biparatopic DARPin bi53_79 and directly compared them to the established anti-IgE antibody omalizumab. Methods: IgE:FcεRI complex dissociation was analyzed in vitro using recombinant proteins in ELISA and surface plasmon resonance, ex vivo using human primary basophils with flow cytometry and in vivo using human FcεRI transgenic mice in a functional passive cutaneous anaphylaxis test. Results We show that E2_79 mediated removal of IgE from primary human basophils fully abrogates IgE-dependent cell activation and release of pro-inflammatory mediators ex vivo. Furthermore, we report that omalizumab also accelerates the dissociation of IgE from FcεRI albeit much less efficiently than E2_79. Using the biparatopic IgE targeting approach we further improved the disruptive potency of E2_79 by ~100 fold and show that disruptive IgE inhibitors efficiently prevent passive cutaneous anaphylaxis in mice expressing the human FcεRI alpha chain. Conclusion Our findings highlight the potential of such novel IgE inhibitors as important diagnostic and therapeutic tools to managing allergic diseases.

The Effect of Omalizumab on Eosinophilic Inflammation of the Respiratory Tract in Patients with Allergic Asthma

“…Eggel et al [24] in their study revealed that omalizumab not only neutralizes free IgE and decreases expression but also might accelerate dissociation of IgE from FceRI on basophils. This observation was confirmed by Serrano-Candelas et al [25] on mast cells.…”

The future of biologics: Applications for food allergy

“…164 In a recent study, treatment with a novel DARPin (E2_79) rapidly disrupted IgE-FcεRI complexes on the surface of basophils and blocked IgE-dependent responses in a humanized mouse model of passive anaphylaxis. 165 In the same study, treatment with a bivalent DARPin (bi53_79), or two DARPins fused together, was more efficacious in reducing anaphylaxis than omalizumab. While studies of DARPins in the treatment of allergy are in their infancy, and future clinical trials are needed to test their safety and efficacy, these disruptive IgE inhibitors may be ideal therapeutics due to their potency and potential to reduce allergic symptoms.…”

IgE and Mast Cells

“…Peptidebased mimicry of IgE or FcεRI components can disrupt the interaction between IgE and its receptor, but the bioavailability and pharmacokinetic characteristics of peptides are not optimal and they are some ways from clinical testing (Eggel et al, 2014;Zhou et al, 2013). Monoclonal antibodies, including omalizumab, have shown promise (Logsdon & Oettgen, 2015).…”