Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange

Luke F. Pennington, Svetlana Tarchevskaya, Daniel Brigger, Karthik Sathiyamoorthy, Michelle T. Graham, Kari Christine Nadeau, Alexander Eggel and Theodore S. Jardetzky ()
Additional contact information
Luke F. Pennington: Stanford University School of Medicine
Svetlana Tarchevskaya: Stanford University School of Medicine
Daniel Brigger: Immunology and Allergology, University Hospital Bern
Karthik Sathiyamoorthy: Stanford University School of Medicine
Michelle T. Graham: Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine
Kari Christine Nadeau: Progam in Immunology, Stanford University School of Medicine
Alexander Eggel: Immunology and Allergology, University Hospital Bern
Theodore S. Jardetzky: Stanford University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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.

Date: 2016
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms11610 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11610

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms11610

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().