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. 2025 May;155(5):1595-1606.e10.
doi: 10.1016/j.jaci.2024.12.1094. Epub 2025 Jan 13.

Antigenic determinants underlying IgE-mediated anaphylaxis to peanut

Scott A Smith  1 , Yasmin W Khan  2 , Rebecca A Shrem  3 , Jonathan A Hemler  4 , Joshua E Doyle  5 , Jacob Daniel  5 , Jian Zhang  5 , Glorismer Pena-Amelunxen  6 , Lorenz Aglas  6 , Robert G Hamilton  7 , Robert Getts  8 , Hugh A Sampson  9 , Joyce J W Wong  10 , Derek Croote  10 , R Stokes Peebles Jr  5 , Benjamin W Spiller  11
Affiliations
Free article

Antigenic determinants underlying IgE-mediated anaphylaxis to peanut

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

Abstract

Background: Studies of human IgE and its targeted epitopes on allergens have been very limited. We established a method to immortalize IgE-encoding B cells from patients with allergy.

Objective: We sought to develop an unbiased and comprehensive panel of peanut-specific human IgE mAbs to characterize key immunodominant antigenic regions and epitopes on peanut allergens to map molecular interactions responsible for inducing anaphylaxis.

Methods: Using human hybridoma technology to immortalize IgE-encoding B cells from peripheral blood of subjects with severe peanut allergy, we generated a panel of naturally occurring human IgE mAbs in an unbiased manner. Isolated IgE mAbs were characterized extensively in allergen binding assays, peptide array analysis, antigenic mapping, binding kinetic analysis, serum blocking, skin testing inhibition, and functional assessment using human FCεRI transgenic mice.

Results: We created a large panel of 54 peanut-specific IgE mAbs, of which 63% were specific for Ara h 2 and/or Ara h 6. Pairs of IgE mAbs with the same antigen specificity but different binding sites were able to mediate passive systemic anaphylaxis in FCεRI transgenic mice. A single mAb targeting the repetitive motif on Ara h 2 was able to induce degranulation and anaphylaxis on its own. IgG1 switch variant immunoglobulins of the IgE mAb inhibited binding of 30% to 60% of patients' IgE to peanut extract (ImmunoCAP) and reduced peanut extract-induced skin wheal sizes by 1.6 to 7.4 mm in patients with peanut allergy.

Conclusion: We created a molecular 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; anaphylaxis; mAb; peanut.

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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.), the Stanley Cohen Innovation Fund, and Vanderbilt University Clinical Translational Science Award UL1TR000445. The authors acknowledge Food Allergy Research & 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” (US 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.