Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange.

Autor:	Pennington LF; Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.; Progam in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.; Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA., Tarchevskaya S; Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.; Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA., Brigger D; Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern 3012, Switzerland.; Department of Clinical Research, University of Bern, Bern 3012, Switzerland., Sathiyamoorthy K; Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.; Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA., Graham MT; Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA., Nadeau KC; Progam in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.; Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA.; Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA., Eggel A; Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern 3012, Switzerland.; Department of Clinical Research, University of Bern, Bern 3012, Switzerland., Jardetzky TS; Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.; Progam in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.; Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine, Stanford, California 94305, USA.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2016 May 19; Vol. 7, pp. 11610. Date of Electronic Publication: 2016 May 19.
DOI:	10.1038/ncomms11610
Abstrakt:	Omalizumab is a widely used therapeutic anti-IgE antibody. Here we report the crystal structure of the omalizumab-Fab in complex with an IgE-Fc fragment. This structure reveals the mechanism of omalizumab-mediated inhibition of IgE interactions with both high- and low-affinity IgE receptors, and explains why omalizumab selectively binds free IgE. The structure of the complex also provides mechanistic insight into a class of disruptive IgE inhibitors that accelerate the dissociation of the high-affinity IgE receptor from IgE. We use this structural data to generate a mutant IgE-Fc fragment that is resistant to omalizumab binding. Treatment with this omalizumab-resistant IgE-Fc fragment, in combination with omalizumab, promotes the exchange of cell-bound full-length IgE with omalizumab-resistant IgE-Fc fragments on human basophils. This combination treatment also blocks basophil activation more efficiently than either agent alone, providing a novel approach to probe regulatory mechanisms underlying IgE hypersensitivity with implications for therapeutic interventions.
Databáze:	MEDLINE
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