6. IgE and IgE-receptor targeting therapies for treating allergies
Another group of antibodies that prevent histamine release by basophils and mast cells are the anti-IgE antibodies. They exert their effect by preventing IgE from binding to FcεRI and CD23 (Figure 1 and 2). Binding of IgE to CD23 may involve different portions of CD23 and, interestingly can be blocked with Omailizumab which also blocks IgE binding to the high affinity receptor for IgE 71. In addition, anti-IgE has a similar inhibitory effect as AIT-induced IgG and IgA antibodies that block IgE-mediated T cell activation130.
The structures of the ectodomain regions of FcεRI and CD23 in complexes with IgE-Fc have revealed how these two distinct receptors interact with IgE97,131,132. IgE binding to its two receptors is regulated through unique conformational changes in the IgE-Fc domain that enable an allosteric competition between low and high-affinity receptors131,133. IgE binding to FcεRI occurs through the tips of the two IgE Cε3 domains, engaging both antibody heavy chains in an asymmetric ”open” conformation 132,133 In contrast, CD23 binding occurs to a distinct surface of the IgE-Fc at the junction between Cε3-Cε4 domains and favours a ”closed” conformation that inhibits FcεRI binding131. High affinity binding to FcεRI leads to the prebinding of serum IgE to receptor-expressing cells, sensitizing them to respond upon allergen exposure and cross-linking. In contrast, IgE binding to CD23 is of lower affinity and is stabilised through avidity effects, most notably by IgE-allergen complex formation. Strikingly, IgE bound to FcεRI is incredibly stable, persisting on peripheral mast cells for weeks-months and impacting the safety and speed of AIT/OIT approaches.
Two anti-IgE antibodies, omalizumab and ligelizumab134,135 have been advanced as therapeutics for the treatment of allergic diseases, including allergic asthma, chronic spontaneous urticaria, chronic rhinosinusitis and food allergies. However, other anti-IgE antibodies are in clinical development (e.g. Xmab7195/UB221/omalizumab biosimilars). Omalizumab and ligelizumab highlight the impressive impact that anti-IgE can have in allergy treatment136. Omalizumab was the first anti-IgE developed as a therapeutic, initially for the treatment of severe allergic asthma in 2003. Since then, omalizumab has shown efficacy in treating CSU, food allergy and chronic rhinosinusitis137. As discussed elsewhere in this review, omalizumab enhanced OIT treatment in food allergy clinical trials, reducing allergen challenge reactions and enabling a more rapid increase in allergen dosing and simultaneous tolerization for multiple allergens138. Ligelizumab is a next-generation, higher affinity anti-IgE that shows an improved ability to suppress free IgE in patients135. Despite having an ~100-fold higher affinity for IgE, ligelizumab surprisingly did not show improved efficacy in treating allergic asthma patients139,140. However, in phase II clinical studies, ligelizumab showed improved efficacy over omalizumab for the treatment of CIU141. It remains to be established whether ligelizumab will have a significant benefit in OIT/AIT relative to omalizumab.
The structures and mechanisms of omalizumab vs ligelizumab are revealing and provide insight into the possible differences in their therapeutic impact. Omalizumab and ligelizumab both engage epitopes in the IgE Cε3 domains adjacent to the binding site for FcεRI139,142,143. Despite the substantial overlap in their epitopes, ligelizumab binds across the IgE dimer engaging residues in both Cε3 domains and overlapping the space that would be occupied by FcεRI. In contrast, omalizumab engages an epitope towards an outer face of the Cε3 domains, does not bind across the IgE dimer and lies somewhat peripherally to FcεRI. One of the consequences of these distinct binding interactions is that omalizumab can effectively inhibit binding to FcεRI and CD23, while ligelizumab shows preferential inhibition of FcεRI139. The ability of ligelizumab to block CD23 binding is weaker than omalizumab, despite its much higher IgE affinity. The weaker inhibition of IgE:CD23 interactions exhibited by ligelizumab may account for its failure to outperform omalizumab in clinical trials for allergic asthma 139,140, where CD23 is thought to play an essential role in disease through antigen presentation and or antigen transport144,145. CD23 has also been studied as a target in allergic diseases. However, although a phase 1/2 study with the anti-CD23 mAb Lumiliximab in asthma patients showed a good safety profile, anti-CD23 has not been developed further in asthma or allergy 146.
It will be exciting and informative to compare the activities of omalizumab and ligelizumab in AIT, which may help assess the clinical importance of the inhibition of CD23 and FcεRI interactions during tolerization to food or other allergens.
The rationale of combining anti-IgE with AIT or OIT is that the combination may prevent allergic side effects of AIT130 and OIT, allow more rapid updosing of allergen, and will provide immediate clinical benefit. Since 2007, several studies have addressed this combination treatment. These are reviewed in detail in 138,148. Overall, both these combination treatments have shown promising results, especially evidenced by decreased adverse reactions to AIT and OIT. Larger follow up studies are needed to define the optimal dosing and target groups for this type of combination treatment.
Finally, a class of ”disruptive” IgE inhibitors has been described based on Designed Ankyrin Repeat Proteins (DARPins), which can rapidly dissociate FcεRI-bound IgE in vitro and in vivo149,150. Such kinetically active anti-IgE inhibitors may have the potential to rapidly desensitise peripheral mast cells and significantly accelerate the timelines for AIT in the future.