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

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. 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.

Authors:
ORCiD logo [1];  [1];  [2];  [1];  [1];  [1];  [2];  [1]
  1. Stanford Univ. School of Medicine, Stanford, CA (United States)
  2. Univ. of Bern, Bern (Switzerland)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1299090
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Pennington, Luke F., Tarchevskaya, Svetlana, Brigger, Daniel, Sathiyamoorthy, Karthik, Graham, Michelle T., Nadeau, Kari Christine, Eggel, Alexander, and Jardetzky, Theodore S. Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange. United States: N. p., 2016. Web. doi:10.1038/ncomms11610.
Pennington, Luke F., Tarchevskaya, Svetlana, Brigger, Daniel, Sathiyamoorthy, Karthik, Graham, Michelle T., Nadeau, Kari Christine, Eggel, Alexander, & Jardetzky, Theodore S. Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange. United States. doi:10.1038/ncomms11610.
Pennington, Luke F., Tarchevskaya, Svetlana, Brigger, Daniel, Sathiyamoorthy, Karthik, Graham, Michelle T., Nadeau, Kari Christine, Eggel, Alexander, and Jardetzky, Theodore S. Thu . "Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange". United States. doi:10.1038/ncomms11610. https://www.osti.gov/servlets/purl/1299090.
@article{osti_1299090,
title = {Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange},
author = {Pennington, Luke F. and Tarchevskaya, Svetlana and Brigger, Daniel and Sathiyamoorthy, Karthik and Graham, Michelle T. and Nadeau, Kari Christine and Eggel, Alexander and Jardetzky, Theodore S.},
abstractNote = {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.},
doi = {10.1038/ncomms11610},
journal = {Nature Communications},
number = ,
volume = 7,
place = {United States},
year = {2016},
month = {5}
}

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