Covalent heterobivalent inhibitor effectively inhibits anaphylaxis to peanut allergen in a humanized mouse model

Abstract

Abstract Peanut-induced allergy is an IgE-mediated type I hypersensitivity reaction that manifests symptoms ranging from local edema to life-threatening anaphylaxis. While there are treatments for symptoms in allergic patients resulting from allergen exposure, there are few preventive therapies other than avoidance and no allergen specific therapies. We have previously designed a covalent heterobivalent inhibitor (cHBI) that binds in an allergen-specific manner as a preventive for allergic reactions. Building on previous in vitro testing, in this report we have developed a humanized mouse model to test cHBI efficacy in vivo. Humanized mice (NSG-SCF/GM-CSF/IL-3) developed mature functional human mast cells in various tissues and developed robust anaphylactic reactions when passively sensitized with human IgE monoclonal antibodies specific for peanut allergen. We found that the allergic response is IgE dose-dependent and is mediated by human mast cells indicated by elevated tryptase serum levels and the upregulation of mast cell degranulation markers. Using the validated humanized mouse model, we showed that cHBI inhibited IgE-mediated anaphylaxis and human mast cell degranulation. We demonstrated that cHBI effectively inhibits anaphylaxis for up to 14 days, and cHBI inhibition is specific to peanut allergen. Importantly, cHBI rescued the mice from lethal anaphylactic response during oral peanut-induced anaphylaxis. These findings suggest that cHBI has the potential to be an effective preventative for peanut food allergy in patients.