Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab.
(2017) J Biol Chem 292: 9975-9987
Authors: Davies, A.M., Allan, E.G., Keeble, A.H., Delgado, J., Cossins, B.P., Mitropoulou, A.N., Pang, M.O.Y., Ceska, T., Beavil, A.J., Craggs, G., Westwood, M., Henry, A.J., McDonnell, J.M., Sutton, B.J.
Abstract
Immunoglobulin E and its interactions with receptors Fc?RI and CD23 play a central role in allergic disease. Omalizumab, a clinically approved therapeutic antibody, inhibits the interaction between IgE and Fc?RI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each C?3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the C?3 domains that inhibit the interaction with Fc?RI. CD23 binding is inhibited sterically due to overlapping binding sites on each C?3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for Fc?RI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from Fc?RI, exploiting the intrinsic flexibility and allosteric potential of IgE.
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