Allosteric Mechanism of Action of the Therapeutic Anti-IgE Antibody Omalizumab

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2017 Apr 26

PMID 28438838

Citations 31

Authors

Anna M Davies

Elizabeth G Allan

Anthony H Keeble

Jean Delgado

Benjamin P Cossins

Alkistis N Mitropoulou

Marie O Y Pang

Tom Ceska

Andrew J Beavil

Graham Craggs

Marta Westwood

Alistair J Henry

James M McDonnell

Brian J Sutton

Affiliations

Soon will be listed here.

Abstract

Immunoglobulin E and its interactions with receptors FcϵRI and CD23 play a central role in allergic disease. Omalizumab, a clinically approved therapeutic antibody, inhibits the interaction between IgE and FcϵRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cϵ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cϵ3 domains that inhibit the interaction with FcϵRI. CD23 binding is inhibited sterically due to overlapping binding sites on each Cϵ3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcϵRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcϵRI, exploiting the intrinsic flexibility and allosteric potential of IgE.

Citing Articles

The Crystal Structure of Human IgD-Fc Reveals Unexpected Differences With Other Antibody Isotypes.

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Allosteric inhibition of IgE-FcεRI interactions by simultaneous targeting of IgE F(ab')2 epitopes.

Hirano T, Koyanagi A, Ago H, Yamamoto M, Kitaura J, Kasai M Commun Biol. 2024; 7(1):1042.

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Eggel A, Pennington L, Jardetzky T Immunol Rev. 2024; 328(1):387-411.

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IgE Immune Complexes Mitigate Eosinophilic Immune Responses through NLRC4 Inflammasome.

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Falcon R, Caoili S Front Allergy. 2023; 4:1215616.

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