Trapping IgE in a closed conformation by mimicking CD23 binding prevents and disrupts FcεRI interaction

Area of Science:

• Immunology
• Structural Biology
• Allergy Research

Background:

• Immunoglobulin E (IgE) plays a central role in allergic responses by binding to FcεRI and CD23 receptors on effector cells.
• Anti-IgE therapeutics aim to disrupt IgE-mediated signaling pathways.

Purpose of the Study:

• To elucidate the structural mechanism by which an anti-IgE single-domain antibody inhibits IgE interactions with its receptors.
• To understand how this inhibition impacts IgE binding and downstream allergic responses.

Main Methods:

• X-ray crystallography to determine the structure of the anti-IgE antibody in complex with an IgE Fc fragment.
• Solution scattering studies to analyze conformational changes in the IgE Fc fragment upon antibody binding.
• Functional assays to assess allergen-mediated basophil activation and IgE receptor displacement.

Main Results:

• The crystal structure reveals the antibody's epitope, overlapping significantly with the CD23-binding site and slightly with the FcεRI-binding site.
• Antibody binding induces a novel half-bent conformation of the IgE Fc fragment, distinct from known conformations.
• The antibody displaces IgE from both FcεRI and CD23 receptors, abrogating allergen-induced basophil activation.

Conclusions:

• The anti-IgE antibody functions as a CD23 homolog, inducing a closed IgE Fc conformation that prevents FcεRI binding.
• This structural and functional insight provides a basis for developing novel anti-IgE therapeutics for allergic diseases.