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

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. Immunoglobulin E (IgE) plays a central role in allergic responses, yet therapeutic targeting of IgE with antibodies such as omalizumab is met with various limitations. Here the authors characterize the molecular properties and crystal structure of a new anti-IgE antibody, ligelizumab, for mechanistic insights related to its enhanced suppression activity.