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

Preview

Text ncomms11610.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (1MB) | Preview

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.

Interest & Impact

Downloads

186 since deposited on 17 May 2017
21 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item