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. 2025 May;155(5):1547-1556.e3.
doi: 10.1016/j.jaci.2024.12.1095. Epub 2025 Jan 11.

Structural determinants of peanut-induced anaphylaxis

Scott A Smith  1 , Rebecca A Shrem  2 , Bruno B C Lança  1 , Jian Zhang  1 , Joyce J W Wong  3 , Derek Croote  3 , R Stokes Peebles Jr  1 , Benjamin W Spiller  4
Affiliations
Free article

Structural determinants of peanut-induced anaphylaxis

Scott A Smith et al. J Allergy Clin Immunol. 2025 May.
Free article

Abstract

Background: Human IgE mAbs recognizing peanut allergens have recently become available, but we lack a detailed understanding of how these IgEs target allergens.

Objective: We sought to determine the molecular details of the antibody-allergen interaction for a panel of clinically important human IgE mAbs and to develop strategies to disrupt disease causing antibody-allergen interactions.

Methods: We identified candidates from a panel of epitope binned human IgE mAbs that recognize 2 important and homologous peanut allergens, Ara h 2 and Ara h 6. Crystal structures were determined revealing the interfaces (antigenic sites) of exemplars of 5 common IgE bins.

Results: Among the common antigenic sites on Ara h 2 and Ara h 6, 2 sites (A and B) are highly conserved between the allergens, explaining the cross-reactivity of antibodies that recognize these sites. Three sites (C, D, and F) involve residues that are not conserved between the allergens. Of the 5 common sites, 3 sites (B, C, and D) involve residues that are near each other only when the allergens are properly folded, such that these sites are conformational. Two additional sites (sites A and F) involve largely linear stretches of amino acids. Site F targeted antibody, 38B7, binds to a peptide sequence DPYSPOHS, in which hydroxylation of the last proline is critical for binding. This sequence is repeated 2 or 3 times depending on the Ara h 2 isoform, enabling 38B7 to induce anaphylaxis as a single mAb, without a second antibody. We have mutated key residues in each site and created a panel of hypoallergens, having reduced IgE mAb binding and lacking the ability to induce anaphylaxis in our murine model.

Conclusion: We created a structural map of the IgE antibody response to the most important peanut allergen proteins to enable the design of new allergy immunotherapies and vaccines.

Keywords: IgE; allergy; anaphylaxis; epitope; mAb.

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Conflict of interest statement

Disclosure statement This work was supported by research grants from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases R01AI155668, R01AI130459, R21AI123307 (to S.A.S.), Vanderbilt University Clinical Translational Science Award UL1TR000445 (to S.A.S.), and Vanderbilt UniversityDiscovery Grant (to B.W.S.). The authors acknowledge Food Allergy Research and Education (FARE) for their support of this work via Clinical Network grants (to J.A.H.). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Disclosure of potential conflict of interest: S. A. Smith receives royalties for intellectual property licenses with InBio and consulting fees from IgGenix Inc. He is an inventor on a patent entitled “Generation of human allergen- and helminth-specific IgE monoclonal antibodies for diagnostic and therapeutic use” (U.S. patent no. US10908168-B2), with royalties paid, and on a pending patent entitled “Generation of human peanut allergen-specific IgE monoclonal antibodies for diagnostic and therapeutic use” (63/159,764), with royalties paid. B. W. Spiller is a co-founder and principal at Turkey Creek Biotechnology. Turkey Creek Biotechnology was not involved in this work. J. J. W. Wong and D. Croote are employees of, and shareholders in, IgGenix Inc.

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