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.

doi:10.1038/ncomms11610

Title: Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange

Journal Article · Thu May 19 00:00:00 EDT 2016 · Nature Communications

DOI:https://doi.org/10.1038/ncomms11610· OSTI ID:1299090

^[1]; Tarchevskaya, Svetlana ^[1]; Brigger, Daniel ^[2]; Sathiyamoorthy, Karthik ^[1]; Graham, Michelle T. ^[1]; Nadeau, Kari Christine ^[1]; Eggel, Alexander ^[2]; Jardetzky, Theodore S. ^[1]

Stanford Univ. School of Medicine, Stanford, CA (United States)
Univ. of Bern, Bern (Switzerland)

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. Furthermore, 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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1299090

Journal Information:: Nature Communications, Vol. 7; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 64 works

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