Allosteric inhibition of IgE–FcεRI interactions by simultaneous targeting of different epitopes on IgE F(ab’)2

Abstract

Abstract Immunoglobulin E (IgE) plays pivotal roles in allergic diseases through interaction with a high-affinity receptor (FcεRI). We established that Fab fragments of anti-IgE antibodies (HMK-12 Fab) rapidly dissociate preformed IgE-FcεRI complexes in a temperature-dependent manner and inhibit IgE-mediated anaphylactic reactions, even after an allergen challenge. X-ray crystallographic studies revealed that the light and heavy chains of HMK-12 Fab interact with the Cε2 homodimer domain and light chain of IgE F(ab’)2, respectively. Consequently, complex formation resulted in a decrease in the asymmetric structural features of IgE Fc domains and the dissociation of IgE. This unexpected finding of the allosteric inhibition of IgE-FcεRI interactions by simultaneous targeting of different epitopes on IgE F(ab’)2 has implications for the development of novel therapies for allergic diseases.