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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Eggel, Alexander¹  Baravalle, Guenther²  Hobi, Gabriel¹  Kim, Beomkyu³  Buschor, Patrick¹  Forrer, Patrik⁴  Shin, Jeoung-Sook²  Vogel, Monique¹  Stadler, Beda M.¹  Dahinden, Clemens A.¹  Jardetzky, Theodore S.³ 

[1] Univ Bern, Inst Immunol, CH-3012 Bern, Switzerland

[2] Univ Calif San Francisco, Sandler Asthma Basic Res Ctr, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[3] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA

[4] Mol Partners AG, Zurich, Switzerland

关键词: Allergy;    basophils;    mast cells;    IgE;    Fc epsilon RI alpha;    designed ankyrin repeat proteins;    inhibitors;   

DOI  :  10.1016/j.jaci.2014.02.005

来源: Elsevier

【 摘 要 】

Background: The remarkably stable interaction of IgE with its high-affinity receptor Fc epsilon RI on basophils and mast cells is critical for the induction of allergic hypersensitivity reactions. Because of the exceptionally slow dissociation rate of IgE-Fc epsilon RI 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 Fc epsilon RI through a molecular mechanism termed facilitated dissociation. Objective: Here we assessed the therapeutic potential of this non-immunoglobulin-based IgE inhibitor E2_79, a designed ankyrin repeat protein (DARPin), as well as a novel engineered biparatopic DARPin bi53_79, and directly compared them with the established anti-IgE antibody omalizumab. Methods: IgE-Fc epsilon RI complex dissociation was analyzed in vitro by using recombinant proteins in ELISA and surface plasmon resonance, ex vivo by using human primary basophils with flow cytometry, and in vivo by using human Fc epsilon RI alpha-chain 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 proinflammatory mediators ex vivo. Furthermore, we report that omalizumab also accelerates the dissociation of IgE from Fc epsilon eRI, although much less efficiently than E2_79. Using the biparatopic IgE targeting approach, we further improved the disruptive potency of E2_79 by approximately 100-fold and show that disruptive IgE inhibitors efficiently prevent passive cutaneous anaphylaxis in mice expressing the human Fc epsilon RI alpha-chain. Conclusion: Our findings highlight the potential of such novel IgE inhibitors as important diagnostic and therapeutic tools for management of allergic diseases.

【 授权许可】

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