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

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's tyrosine kinase (BTK) can rapidly act 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 the next day. Post-challenge, mice received acalabrutinib and/or other rescue treatments via intraperitoneal injection. The 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 post-challenge, with 100% survival compared to 29% survival of mice receiving vehicle control. Additionally, acalabrutinib synergized with epinephrine and formoterol in preventing mortality at 5 minutes post-challenge. Serum prostaglandin D2 and leukotriene E4 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 given in conjunction with epinephrine for the treatment of anaphylaxis.