Structural and Functional Insights Into IgE Receptor Interactions and Disruptive Inhibition.

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.