Targeting the FcεRI Pathway as a Potential Strategy to Prevent Food-Induced Anaphylaxis

Abstract

Despite attempts to halt it, the prevalence of food allergy is increasing, and there is an unmet need for strategies to prevent morbidity and mortality from food-induced allergic reactions. There are no known medications that can prevent anaphylaxis, but several novel therapies show promise for the prevention of food-induced anaphylaxis through targeting of the high-affinity IgE receptor (FcϵRI) pathway. This pathway includes multiple candidate targets, including tyrosine kinases and the receptor itself. Small molecule inhibitors of essential kinases have rapid onset of action and transient efficacy, which may be beneficial for short-term use for immunotherapy buildup or desensitizations. Short courses of FDA-approved inhibitors of Bruton’s tyrosine kinase can eliminate IgE-mediated basophil activation and reduce food skin test size in allergic adults, and prevent IgE-mediated anaphylaxis in humanized mice. In contrast, biologics may provide longer-lasting protection, albeit with slower onset. Omalizumab is an anti-IgE antibody that sequesters IgE, thereby reducing FcϵRI expression on mast cells and basophils. As a monotherapy, it can increase the clinical threshold dose of food allergen, and when used as an adjunct for food immunotherapy, it decreases severe reactions during buildup phase. Finally, lirentelimab, an anti-Siglec-8 antibody currently in clinical trials, can prevent IgE-mediated anaphylaxis in mice through mast cell inhibition. This review discusses these and other emerging therapies as potential strategies for preventing food-induced anaphylaxis. In contrast to other food allergy treatments which largely focus on individual allergens, blockade of the FcϵRI pathway has the advantage of preventing clinical reactivity from any food.

Findings of in vitro Analyses of Basophil Functions May Help Us Better Understand Drug Desensitization

“…Second, we did not test mast cell functions, but we note that precise characterization of ex vivo mast cell desensitization is a very difficult task. In addition, our analyses did not elucidate activation markers such as CD63 or CD203c, or the intracellular signals that induce basophil desensitization, although other researchers are accumulating findings through active scrutiny of human basophils ( 3 , 5 – 8 ). Moreover, we do not know the extent to which desensitization induced by exposure to subthreshold allergen is similar or related to that induced by high–dose allergen.…”

FcεRI: A Master Regulator of Mast Cell Functions

“…FcεRI has been targeted for clinical benefits to inhibit or attenuate MC degranulation, and effective clinical approaches for suppressing IgE-dependent MC activation have emerged [ 51 , 52 ]. Omalizumab, a humanized anti-IgE monoclonal antibody that binds to the Cε3 domain of IgE, can prevent the binding of circulating IgE to FcεRI, is a common and preferred treatment (especially for chronic urticaria), and is effective against asthma [ 53 , 54 , 55 ].…”

“…Regarding other antibody antagonism/antibody neutralization, ligelizumab is another potent humanized anti-IgE monoclonal antibody that binds to free IgE with a higher affinity than omalizumab. Ligelizumab binds to the C3 domain of IgE, but unlike omalizumab, it can also bind to IgE-bound to CD23, a low-affinity IgE receptor expressed on B cells [ 51 , 69 ]. In 2020, Gasser et al demonstrated the structural and mechanistic differences between ligelizumab and omalizumab, where they report epitope differences between the anti-IgE antibodies and indicate the differences contribute to their qualitatively distinct IgE-receptor inhibition profiles [ 69 ].…”

“…Ankyrin-repeat domain binding can affect the stability and effector functions of target proteins. The motivation for engineering DARPins was to generate binding proteins that can be used to target proteins with high affinity and specificity, essentially replacing the use of monoclonal antibodies [ 51 , 70 ]. Therefore, the advantage of anti-IgE DARPins is that they not only neutralize free IgE but also actively disrupt pre-formed IgE–FcεRI complexes through a facilitated dissociation mechanism [ 63 , 71 ].…”

Immediate Hypersensitivity Reactions Induced by COVID-19 Vaccines: Current Trends, Potential Mechanisms and Prevention Strategies

“…Recently, IL-4 and IL-13 inhibitors such as dupilumab have been used to treat anaphylaxis by inhibiting mast cell expansion. These biological agents may be adjuncts in difficult-to-treat patients with immediate hypersensitivity and anaphylaxis [ 115 , 116 ]. Further clinical trials are needed to determine whether these medicines and biologic agents can be successfully used to treat patients with COVID-19-vaccine-induced immediate hypersensitivity or anaphylaxis.…”