Structural basis for selective inhibition of immunoglobulin E-receptor interactions by an anti-IgE antibody

Jiun-Bo Chen,James M Mcdonnell,Andrew J Beavil,Marie O Y Pang,Anna M Davies,Rebecca L Beavil,Hannah J Gould,Brian J Sutton,Mary D Holdom,Tse Wen Chang,Alkistis N Mitropoulou,Faruk Ramadani

doi:10.1038/s41598-018-29664-4

Abstract

Immunoglobulin E (IgE) antibodies play a central role in the allergic response: interaction with FcεRI on mast cells and basophils leads to immediate hypersensitivity reactions upon allergen challenge, while interaction with CD23/FcεRII, expressed on a variety of cells, regulates IgE synthesis among other activities. The receptor-binding IgE-Fc region has recently been found to display remarkable flexibility, from acutely bent to extended conformations, with allosteric communication between the distant FcεRI and CD23 binding sites. We report the structure of an anti-IgE antibody Fab (8D6) bound to IgE-Fc through a mixed protein-carbohydrate epitope, revealing further flexibility and a novel extended conformation with potential relevance to that of membrane-bound IgE in the B cell receptor for antigen. Unlike the earlier, clinically approved anti-IgE antibody omalizumab, 8D6 inhibits binding to FcεRI but not CD23; the structure reveals how this discrimination is achieved through both orthosteric and allosteric mechanisms, supporting therapeutic strategies that retain the benefits of CD23 binding.

Highlights

Region of the Cε3 domain distal to the FcεRIα binding site, and near the interface with the Cε4 domain[22,23,28,29]
The open and closed Cε3 domain conformations involved in FcεRIα and CD23 interactions, respectively, preclude simultaneous engagement of both receptors by Immunoglobulin E (IgE)-Fc; binding of FcεRIα and CD23 are regulated in an allosteric manner[22,23,29,30]
The structural basis for the mechanism of action of omalizumab has recently been elucidated[36]; omalizumab inhibits the binding of IgE to FcεRI allosterically, as antibody binding causes the Cε3 domains to adopt a conformation that is too open to permit simultaneous engagement of both FcεRI sub-sites on IgE-Fc36, while the binding of IgE to CD23 is inhibited orthosterically[36,37]

Summary

Introduction

Region of the Cε3 domain distal to the FcεRIα binding site, and near the interface with the Cε4 domain[22,23,28,29]. The structural basis for the mechanism of action of omalizumab has recently been elucidated[36]; omalizumab inhibits the binding of IgE to FcεRI allosterically, as antibody binding causes the Cε3 domains to adopt a conformation that is too open to permit simultaneous engagement of both FcεRI sub-sites on IgE-Fc36, while the binding of IgE to CD23 is inhibited orthosterically[36,37]. Another anti-IgE antibody, MEDI4212, inhibits the interaction between IgE-Fc and its two receptors[21]; binding to FcεRI is inhibited due to steric overlap, while binding to CD23 is inhibited as the Cε3 domains are “locked” in an open conformation[21]. There may be advantages to a therapeutic strategy that combines IgE neutralization and modulation of IgE production simultaneously

Methods

Results

Conclusion