The Journal of allergy and clinical immunology · 2025
Structural determinants of peanut-induced anaphylaxis.
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Smith Scott A, Shrem Rebecca A, Lança Bruno B C, Zhang Jian, Wong Joyce J W, Croote Derek, Peebles R Stokes, Spiller Benjamin W
Аннотация
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.
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.