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Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange

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  • Luke F. Pennington

    (Stanford University School of Medicine
    Progam in Immunology, Stanford University School of Medicine
    Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine)

  • Svetlana Tarchevskaya

    (Stanford University School of Medicine
    Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine)

  • Daniel Brigger

    (Immunology and Allergology, University Hospital Bern
    University of Bern)

  • Karthik Sathiyamoorthy

    (Stanford University School of Medicine
    Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine)

  • Michelle T. Graham

    (Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine
    Stanford University School of Medicine)

  • Kari Christine Nadeau

    (Progam in Immunology, Stanford University School of Medicine
    Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine
    Stanford University School of Medicine)

  • Alexander Eggel

    (Immunology and Allergology, University Hospital Bern
    University of Bern)

  • Theodore S. Jardetzky

    (Stanford University School of Medicine
    Progam in Immunology, Stanford University School of Medicine
    Sean N. Parker Center for Allergy Research at Stanford University, Stanford University School of Medicine)

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.

Suggested Citation

  • Luke F. Pennington & Svetlana Tarchevskaya & Daniel Brigger & Karthik Sathiyamoorthy & Michelle T. Graham & Kari Christine Nadeau & Alexander Eggel & Theodore S. Jardetzky, 2016. "Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11610
    DOI: 10.1038/ncomms11610
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    Cited by:

    1. Luke F. Pennington & Pascal Gasser & Silke Kleinboelting & Chensong Zhang & Georgios Skiniotis & Alexander Eggel & Theodore S. Jardetzky, 2021. "Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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