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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.
Highlights
Targeting of immunoglobulin E (IgE) represents an interesting approach for the treatment of allergic disorders
While this FcεRI-dependent cellular degranulation process accounts for immediate hypersensitivity reactions and the induction of clinical allergy symptoms, the interaction of IgE with CD23 has been reported to be involved in antigen presentation, the transport of antigens across airway and intestinal epithelial barriers and the regulation of IgE synthesis[10,11,12,13]
Given the difference in their binding epitopes on IgE, we further explored the ability of ligelizumab and omalizumab to inhibit IgE-binding to CD23
Summary
Targeting of immunoglobulin E (IgE) represents an interesting approach for the treatment of allergic disorders. Exposure to allergens induces cross-linking of IgE-bound FcεRI resulting in immediate activation of allergic effector cells, which culminates in cellular degranulation and the release of vasoactive and pro-inflammatory mediators[9] While this FcεRI-dependent cellular degranulation process accounts for immediate hypersensitivity reactions and the induction of clinical allergy symptoms, the interaction of IgE with CD23 has been reported to be involved in antigen presentation, the transport of antigens across airway and intestinal epithelial barriers and the regulation of IgE synthesis[10,11,12,13]. Our data provide a structural and mechanistic foundation for understanding why ligelizumab exerts a qualitatively and functionally distinct inhibition profile from omalizumab and is superior in suppressing FcεRI-dependent allergic reactions in vitro, in a passive systemic anaphylaxis mouse model in vivo and in clinical studies with chronic spontaneous urticaria patients[31]
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