The mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab

Pascal Gasser, Svetlana S. Tarchevskaya, Pascal Guntern, Daniel Brigger, Rahel Ruppli, Noemi Zbären, Silke Kleinboelting, Christoph Heusser, Theodore S. Jardetzky () and Alexander Eggel ()
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Pascal Gasser: University of Bern
Svetlana S. Tarchevskaya: Stanford University School of Medicine
Pascal Guntern: University of Bern
Daniel Brigger: University of Bern
Rahel Ruppli: University of Bern
Noemi Zbären: University of Bern
Silke Kleinboelting: Stanford University School of Medicine
Christoph Heusser: Pharmaceutical Research, Novartis AG
Theodore S. Jardetzky: Stanford University School of Medicine
Alexander Eggel: University of Bern

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Targeting of immunoglobulin E (IgE) represents an interesting approach for the treatment of allergic disorders. A high-affinity monoclonal anti-IgE antibody, ligelizumab, has recently been developed to overcome some of the limitations associated with the clinical use of the therapeutic anti-IgE antibody, omalizumab. Here, we determine the molecular binding profile and functional modes-of-action of ligelizumab. We solve the crystal structure of ligelizumab bound to IgE, and report epitope differences between ligelizumab and omalizumab that contribute to their qualitatively distinct IgE-receptor inhibition profiles. While ligelizumab shows superior inhibition of IgE binding to FcεRI, basophil activation, IgE production by B cells and passive systemic anaphylaxis in an in vivo mouse model, ligelizumab is less potent in inhibiting IgE:CD23 interactions than omalizumab. Our data thus provide a structural and mechanistic foundation for understanding the efficient suppression of FcεRI-dependent allergic reactions by ligelizumab in vitro as well as in vivo.

Date: 2020
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DOI: 10.1038/s41467-019-13815-w

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