Structural determinants of peanut-induced anaphylaxis
Scott A. Smith, Rebecca A. Shrem, Bruno B C Lança, Jian Zhang, Joyce J. W. Wong, Derek Croote, R. Stokes Peebles, Benjamin W. Spiller
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: S, 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.