The Bruton’s tyrosine kinase inhibitor acalabrutinib protects from anaphylaxis in a humanized mouse model

Abstract

There is an unmet need for therapies that can prevent anaphylaxis. Acalabrutinib is a well-tolerated, FDA approved drug for leukemia that targets Bruton’s tyrosine kinase (BTK), an enzyme also thought to be essential for IgE receptor signaling in human mast cells and basophils. We tested the hypothesis that acalabrutinib administration would prevent anaphylaxis in a humanized mouse model. NSG-SGM3 mice were engrafted with human CD34+ cells at age 3-4 weeks. 16 weeks after engraftment, passive systemic anaphylaxis (PSA) was induced by intravenous sensitization with human anti-NP-IgE and challenge 24 hours later with intravenous injection of NP-BSA. Mice were pre-treated with acalabrutinib or vehicle control via oral gavage prior to challenge. Anaphylactic responses were assessed using core body temperature and clinical scoring. NSG-SGM3 mice engrafted with human CD34+ cells showed good engraftment of human mast cells in addition to excellent PSA responses. Increasing the challenge dose of NP-BSA from 5 to 500 μg resulted in increased severity of anaphylaxis, from mild to fatal responses. Two doses of 15 mg/kg acalabrutinib administered 16 and 4 hours prior to challenge completely mitigated, and 1.5 mg/kg partially mitigated, responses to moderate PSA compared to mice gavaged with vehicle. NSG-SGM3 humanized mice represent a unique model for the study of anaphylaxis where the severity of response can be controlled by varying the amount of allergen used for challenge. Furthermore, pretreatment with just two doses of acalabrutinib completely prevented PSA in these mice, suggesting that BTK inhibitors may be able to prevent IgE-mediated anaphylaxis in humans.