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Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex

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  • Luke F. Pennington

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

  • Pascal Gasser

    (University Hospital Bern
    University of Bern)

  • Silke Kleinboelting

    (Stanford University School of Medicine)

  • Chensong Zhang

    (Stanford University School of Medicine)

  • Georgios Skiniotis

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Alexander Eggel

    (University Hospital Bern
    University of Bern)

  • Theodore S. Jardetzky

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

Abstract

Antibody drugs exert therapeutic effects via a range of mechanisms, including competitive inhibition, allosteric modulation, and immune effector mechanisms. Facilitated dissociation is an additional mechanism where antibody-mediated “disruption” of stable high-affinity macromolecular complexes can potentially enhance therapeutic efficacy. However, this mechanism is not well understood or utilized therapeutically. Here, we investigate and engineer the weak disruptive activity of an existing therapeutic antibody, omalizumab, which targets IgE antibodies to block the allergic response. We develop a yeast display approach to select for and engineer antibody disruptive efficiency and generate potent omalizumab variants that dissociate receptor-bound IgE. We determine a low resolution cryo-EM structure of a transient disruption intermediate containing the IgE-Fc, its partially dissociated receptor and an antibody inhibitor. Our results provide a conceptual framework for engineering disruptive inhibitors for other targets, insights into the failure in clinical trials of the previous high affinity omalizumab HAE variant and anti-IgE antibodies that safely and rapidly disarm allergic effector cells.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27397-z
    DOI: 10.1038/s41467-021-27397-z
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    References listed on IDEAS

    as
    1. 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.
    2. Beomkyu Kim & Alexander Eggel & Svetlana S. Tarchevskaya & Monique Vogel & Heino Prinz & Theodore S. Jardetzky, 2012. "Accelerated disassembly of IgE–receptor complexes by a disruptive macromolecular inhibitor," Nature, Nature, vol. 491(7425), pages 613-617, November.
    3. Frederic Jabs & Melanie Plum & Nick S. Laursen & Rasmus K. Jensen & Brian Mølgaard & Michaela Miehe & Marco Mandolesi & Michèle M. Rauber & Wolfgang Pfützner & Thilo Jakob & Christian Möbs & Gregers R, 2018. "Trapping IgE in a closed conformation by mimicking CD23 binding prevents and disrupts FcεRI interaction," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
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    Cited by:

    1. Qu Chen & Rajesh Menon & Lesley J. Calder & Pavel Tolar & Peter B. Rosenthal, 2022. "Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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