Department of BioMedical Research, University of Bern, Bern, Switzerland.
Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern, Switzerland.
Nat Commun. 2020 Jan 8;11(1):165. doi: 10.1038/s41467-019-13815-w.
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.
针对免疫球蛋白 E（IgE）是治疗过敏疾病的一种很有前途的方法。最近开发了一种高亲和力的单克隆抗 IgE 抗体，ligelizumab，以克服与治疗性抗 IgE 抗体omalizumab 临床应用相关的一些限制。在这里，我们确定了 ligelizumab 的分子结合特征和作用模式。我们解析了 ligelizumab 与 IgE 结合的晶体结构，并报告了 ligelizumab 和 omalizumab 之间的表位差异，这些差异导致它们对 IgE 受体的抑制谱存在质的不同。虽然 ligelizumab 显示出对 IgE 与 FcεRI、嗜碱性粒细胞活化、B 细胞 IgE 产生和体内被动全身性过敏反应的结合具有更好的抑制作用，但 ligelizumab 抑制 IgE:CD23 相互作用的效力低于 omalizumab。因此，我们的数据为理解 ligelizumab 在体外和体内有效抑制 FcεRI 依赖性过敏反应提供了结构和机制基础。
