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

Pennington, Luke F; Tarchevskaya, Svetlana; Brigger, Daniel; Sathiyamoorthy, Karthik; Graham, Michelle T; Nadeau, Kari Christine; Eggel, Alexander; Jardetzky, Theodore S (2016). Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange. Nature communications, 7(11610), p. 11610. Nature Publishing Group 10.1038/ncomms11610

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie

UniBE Contributor:

Brigger, Daniel and Eggel, Alexander

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Stefan Kuchen

Date Deposited:

17 May 2017 14:13

Last Modified:

21 May 2017 02:15

Publisher DOI:

10.1038/ncomms11610

PubMed ID:

27194387

BORIS DOI:

10.7892/boris.95680

URI:

https://boris.unibe.ch/id/eprint/95680

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