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. 2025 Jul 17:S0091-6749(25)00774-2.
doi: 10.1016/j.jaci.2025.07.003. Online ahead of print.

The Bruton tyrosine kinase inhibitor acalabrutinib aborts ongoing acute food-induced anaphylactic reactions in humanized mice

Betania Arce  1 , Natalia M Vilela  1 , Kristin L Chichester  1 , Kristina A Sokol  1 , Santiago Alvarez-Arango  2 , Livia Iacobelli  1 , Eric T Oliver  1 , Derek Croote  3 , Bruce S Bochner  4 , Donald W MacGlashan Jr  1 , Melanie C Dispenza  5
Affiliations

The Bruton tyrosine kinase inhibitor acalabrutinib aborts ongoing acute food-induced anaphylactic reactions in humanized mice

Betania Arce et al. J Allergy Clin Immunol. .

Abstract

Background: There is a need for novel rescue therapies that can reduce morbidity and/or mortality from acute anaphylaxis. Given prior data showing that oral inhibitors of Bruton tyrosine kinase (BTK) can act rapidly as preventive agents for food-induced anaphylaxis in mice and humans, we hypothesized that these compounds could also abort ongoing acute IgE-mediated anaphylactic reactions.

Methods: Primary human mast cells and basophils were stimulated with anti-IgE, treated with the BTK inhibitor acalabrutinib, and assessed for activation and degranulation. NSG-SGM3 humanized mice with human mast cells and basophils were sensitized with human anti-Ara h 2 IgE and then orally challenged with peanut. After challenge, the mice received acalabrutinib and/or other rescue treatments via intraperitoneal injection. Anaphylactic response was assessed by core body temperature and clinical scoring. Mast cell and basophil mediators were measured in serum by ELISA at baseline and during anaphylaxis.

Results: Incubation of human mast cells and basophils with acalabrutinib after anti-IgE stimulation stopped ongoing activation as quickly as addition of the calcium chelator EDTA in vitro. Acalabrutinib completely prevented clinical reactivity to peanut in sensitized humanized mice when administered up to 2 minutes after challenge, with 100% survival versus 29% survival among the mice receiving vehicle control. Additionally, acalabrutinib synergized with epinephrine and formoterol in preventing mortality at 5 minutes after challenge. Serum prostaglandin D2 and leukotriene E4 levels were significantly decreased with acalabrutinib rescue treatment.

Conclusions: Acalabrutinib can stop ongoing IgE-mediated anaphylaxis and prevent mortality in humanized mice. BTK inhibitors could be effective novel rescue medications when given in conjunction with epinephrine for the treatment of anaphylaxis.

Keywords: Acalabrutinib; Bruton tyrosine kinase; anaphylaxis; antihistamines; epinephrine; food allergy; zanubrutinib.

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Conflict of interest statement

Disclosure statement This work was funded by the National Institutes of Health grant AI143965 to M.C.D. Disclosure of potential conflict of interest: M. C. Dispenza has consulted and/or participated on advisory boards for Aditum Bio, ALK, Allakos, Blueprint Medicines, Guidepoint, GLG, Melinta Therapeutics, and Nurix Therapeutics and has received funding from AstraZeneca. E. Oliver has consulted and/or participated on advisory boards for Novartis, Sanofi/Regeneron, and Eli Lilly. D. Croote is an employee of and stakeholder in IgGenix, Inc. The rest of the authors declare that they have no relevant conflicts of interest.

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