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Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange NATURE COMMUNICATIONS Pennington, L. F., Tarchevskaya, S., Brigger, D., Sathiyamoorthy, K., Graham, M. T., Nadeau, K. C., Eggel, A., Jardetzky, T. S. 2016; 7

Abstract

Omalizumab is a widely used therapeutic anti-IgE antibody. Here we report the crystal structure of the omalizumab-Fab in complex with an IgE-Fc fragment. This structure reveals the mechanism of omalizumab-mediated inhibition of IgE interactions with both high- and low-affinity IgE receptors, and explains why omalizumab selectively binds free IgE. The structure of the complex also provides mechanistic insight into a class of disruptive IgE inhibitors that accelerate the dissociation of the high-affinity IgE receptor from IgE. We use this structural data to generate a mutant IgE-Fc fragment that is resistant to omalizumab binding. Treatment with this omalizumab-resistant IgE-Fc fragment, in combination with omalizumab, promotes the exchange of cell-bound full-length IgE with omalizumab-resistant IgE-Fc fragments on human basophils. This combination treatment also blocks basophil activation more efficiently than either agent alone, providing a novel approach to probe regulatory mechanisms underlying IgE hypersensitivity with implications for therapeutic interventions.

View details for DOI 10.1038/ncomms11610

View details for Web of Science ID 000376111500001

View details for PubMedID 27194387

View details for PubMedCentralID PMC4873975