The Use of Bruton’s Tyrosine Kinase Inhibitors to Treat Allergic Disorders

Abstract

Purpose of review Studies show that inhibitors of Bruton’s tyrosine kinase (BTKis), currently FDA-approved for the treatment of B cell malignancies, can prevent IgE-mediated reactions through broad inhibition of the FcεRI signaling pathway in human mast cells and basophils. This review will summarize recent data supporting the use of these drugs as novel therapies in various allergic disorders. Recent findings Recent studies have shown that BTKis can prevent IgE-mediated degranulation and cytokine production in primary human mast cells and basophils. Two oral doses of the second-generation BTKi acalabrutinib can completely prevent moderate passive systemic anaphylaxis in humanized mice and even protect against death during severe anaphylaxis. Furthermore, two doses of ibrutinib can reduce or eliminate skin prick test responses to foods and aeroallergens in allergic subjects. BTKis in development also show efficacy in clinical trials for chronic urticaria. Unlike other therapies targeting IgE, such as omalizumab, BTKis appear to have rapid onset and transient effects, making them ideal candidates for intermittent use to prevent acute reactions such as IgE-mediated anaphylaxis. Summary These studies suggest that BTKis may be capable of preventing IgE-mediated anaphylaxis, paving the way for future trials in food allergy and urticaria.

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

“…One recently completed Phase II clinical trial (NCT03149315) has tested the efficacy of ibrutinib on inhibiting food-induced anaphylaxis in adult patients. The initial results of this trial showed that short-term ibrutinib therapy (as few as 2 doses) suppresses skin test responses and eliminates IgE-mediated basophil activation in adults with peanut or tree nut allergy (59,128). Mechanistically, BTK is essential for FcϵRI signaling and allergic responses in human mast cells and basophils (59,(128)(129)(130)(131).…”

“…The initial results of this trial showed that short-term ibrutinib therapy (as few as 2 doses) suppresses skin test responses and eliminates IgE-mediated basophil activation in adults with peanut or tree nut allergy (59,128). Mechanistically, BTK is essential for FcϵRI signaling and allergic responses in human mast cells and basophils (59,(128)(129)(130)(131). Bone marrow-derived mast cells of Btk -/mice exhibit impaired FcϵRI-mediated production of eicosanoid, leukotriene C4 (LTC4) and reactive oxygen species (ROS) in vitro (132).…”

“…Compared to other drugs commonly used for allergy, ibrutinib and acalabrutinib offer several unique benefits, including the ability to effectively inhibit IgE-FcϵRI-mediated activation of both mast cells and basophils, rapid onset of action and transient efficacy (59,128). Other commonly used allergy drugs do not have the capability to effectively reduce both mast cell and basophil activation (59,128).…”

“…Compared to other drugs commonly used for allergy, ibrutinib and acalabrutinib offer several unique benefits, including the ability to effectively inhibit IgE-FcϵRI-mediated activation of both mast cells and basophils, rapid onset of action and transient efficacy (59,128). Other commonly used allergy drugs do not have the capability to effectively reduce both mast cell and basophil activation (59,128). For example, antihistamines target only one mediator, histamine, of allergy and cannot prevent anaphylaxis, which could be triggered by other mediators (such as prostaglandins, leukotrienes and cytokines) released by activated mast cells and basophils (59,128).…”

State-of-the-Art on Biomarkers for Anaphylaxis in Obstetrics

“…Bruton's tyrosine kinase is an essential kinase for signaling through the high-affinity receptor FcεRI on the surface of mast cells and basophils, the activated signaling cascade causes the release of numerous allergic mediators including histamine, prostaglandins, leukotrienes, and cytokines responsible for inducing signs and symptoms in anaphylaxis [31].…”