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

  • Nat Commun. 2020 Jan 8;11(1):165. doi: 10.1038/s41467-019-13815-w.
Pascal Gasser  1  2  3 ,  Svetlana S Tarchevskaya  4 ,  Pascal Guntern  1  2  3 ,  Daniel Brigger  1  2 ,  Rahel Ruppli  1  2 ,  Noemi Zbären  1  2 ,  Silke Kleinboelting  4 ,  Christoph Heusser  5 ,  Theodore S Jardetzky  6 ,  Alexander Eggel  7  8
Affiliations
  • 1. Department of BioMedical Research, University of Bern, Bern, Switzerland.
  • 2. Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern, Switzerland.
  • 3. Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
  • 4. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 5. Pharmaceutical Research, Novartis AG, 4002, Basel, Switzerland.
  • 6. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA. [email protected].
  • 7. Department of BioMedical Research, University of Bern, Bern, Switzerland. [email protected].
  • 8. Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern, Switzerland. [email protected].
PMID: 31913280 DOI: 10.1038/s41467-019-13815-w
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.

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