Eggel Alexander, Jardetzky Theodore S
Department for BioMedical Research, University of Bern, Bern, Switzerland.
Department of Rheumatology and Immunology, University Hospital Bern, Bern, Switzerland.
Immunol Rev. 2025 May;331(1):e70031. doi: 10.1111/imr.70031.
Immunoglobulin E (IgE) plays a critical role in host defense against parasites and venoms but is also best known for its central involvement in allergic reactions. Through interactions with its high- and low-affinity receptors, FcεRI and CD23, respectively, IgE sensitizes mast cells and basophils, drives antigen presentation, regulates antibody production, and overall amplifies type 2 immunity. The unique conformational flexibility of IgE, particularly within its Cε2-Cε4 domains of the Fc-region, has emerged as a key determinant of receptor specificity and function. Structural studies have revealed that IgE adopts distinct open and closed conformations that selectively enable FcεRI or CD23 binding. These insights have reshaped our understanding of receptor engagement and laid the foundation for therapeutic targeting approaches of IgE:receptor interactions to treat allergies. Initial anti-IgE biologics, such as omalizumab, were developed to neutralize free IgE in circulation and prevent receptor binding. While clinically successful, this approach has limitations, such as the inefficient targeting of receptor-bound IgE and the requirement for prolonged and frequent injections to achieve therapeutic benefit. Recent advances have led to the development of a new class of anti-IgE molecules termed "disruptive" IgE inhibitors that actively disassemble preformed IgE:FcεRI complexes. By exploiting conformational dynamics, creating steric interference, or allosteric mechanisms, these molecules, in addition to their neutralizing capacity, enable rapid active desensitization of allergic effector cells. In this review, we highlight how an improved structural and mechanistic understanding of IgE and its receptors has guided the design of such next-generation anti-IgE molecules. Such multifunctional biologics might offer faster onset, broader activity, and potential use in acute allergic situations, setting the stage for a new era in IgE-targeted therapy.
免疫球蛋白E（IgE）在宿主抵御寄生虫和毒液的防御中发挥着关键作用，但也因其在过敏反应中的核心作用而最为人所知。通过分别与高亲和力和低亲和力受体FcεRI和CD23相互作用，IgE使肥大细胞和嗜碱性粒细胞致敏，驱动抗原呈递，调节抗体产生，并总体上放大2型免疫反应。IgE独特的构象灵活性，特别是在其Fc区域的Cε2 - Cε4结构域内，已成为受体特异性和功能的关键决定因素。结构研究表明，IgE采用不同的开放和闭合构象，选择性地实现与FcεRI或CD23的结合。这些见解重塑了我们对受体结合的理解，并为治疗IgE：受体相互作用以治疗过敏的靶向治疗方法奠定了基础。最初的抗IgE生物制剂，如奥马珠单抗，被开发用于中和循环中的游离IgE并防止受体结合。虽然在临床上取得了成功，但这种方法有局限性，例如对受体结合的IgE靶向效率低下，以及需要长期频繁注射才能获得治疗益处。最近的进展导致了一类新的抗IgE分子的开发，称为“破坏性”IgE抑制剂，它们能主动拆解预先形成的IgE：FcεRI复合物。通过利用构象动力学、产生空间干扰或变构机制，这些分子除了具有中和能力外，还能使过敏效应细胞快速主动脱敏。在这篇综述中，我们强调了对IgE及其受体在结构和机制上的深入理解如何指导了此类下一代抗IgE分子的设计。这种多功能生物制剂可能起效更快、活性更广泛，并有可能用于急性过敏情况，为IgE靶向治疗的新时代奠定基础。
