| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Eggel, Alexander Baravalle, Günther Hobi, Gabriel Kim, Beomkyu Buschor, Patrick Forrer, Patrik Shin, Jeoung-Sook Vogel, Monique Stadler, Beda M. Dahinden, Clemens A. Jardetzky, Theodore S. |
| Description |
Author Affiliation: Eggel A ( Institute of Immunology, University of Bern, Bern, Switzerland. Electronic address: alexander.eggel@iib.unibe.ch.); Baravalle G ( Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, Calif.); Hobi G ( Institute of Immunology, University of Bern, Bern, Switzerland.); Kim B ( Department of Structural Biology, Stanford University School of Medicine, Stanford, Calif.); Buschor P ( Institute of Immunology, University of Bern, Bern, Switzerland.); Forrer P ( Molecular Partners AG, Zürich-Schlieren, Switzerland.); Shin JS ( Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, Calif.); Vogel M ( Institute of Immunology, University of Bern, Bern, Switzerland.); Stadler BM ( Institute of Immunology, University of Bern, Bern, Switzerland.); Dahinden CA ( Institute of Immunology, University of Bern, Bern, Switzerland.); Jardetzky TS ( Department of Structural Biology, Stanford University School of Medicine, Stanford, Calif.) |
| Abstract |
BACKGROUND: The remarkably stable interaction of IgE with its high-affinity receptor FcεRI on basophils and mast cells is critical for the induction of allergic hypersensitivity reactions. Because of 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 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-FcεRI 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 FcεRI -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 FcεRI, 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 FcεRI -chain. CONCLUSION: Our findings highlight the potential of such novel IgE inhibitors as important diagnostic and therapeutic tools for management of allergic diseases. |
| File Format |
HTM / HTML |
| ISSN |
00916749 |
| e-ISSN |
10976825 |
| DOI |
10.1016/j.jaci.2014.02.005 |
| Journal |
Journal of Allergy and Clinical Immunology |
| Issue Number |
6 |
| Volume Number |
133 |
| Language |
English |
| Publisher |
Elsevier |
| Publisher Date |
2014-06-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Discipline Immunology Ankyrin Repeat Immunoglobulin E Metabolism Receptors, Ige Recombinant Fusion Proteins Pharmacology Anaphylaxis Genetics Immunology Prevention & Control Animals Antibodies, Anti-idiotypic Administration & Dosage Chemistry Antibodies, Monoclonal, Humanized Antigens Basophils Dose-response Relationship, Drug Mast Cells Mice Mice, Transgenic Models, Molecular Molecular Mimicry Omalizumab Protein Binding Drug Effects Protein Conformation Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
