Targeting Ara h 2 with human‐derived monoclonal antibodies prevents peanut‐induced anaphylaxis in mice

Abstract

Background: Peanut allergy is a type-I hypersensitivity immune reaction mediated by the binding of peanut allergens to IgE-FcεRI complexes on mast cells and basophils and by their subsequent cellular degranulation. Of all major peanut allergens, Ara h 2 is considered the most anaphylactic. With few options but allergen avoidance, effective treatment of allergic patients is needed. Passive immunotherapy (herein called PIT) based on prophylactic administration of peanut-specific monoclonal antibodies (mAbs) may present a promising treatment option for this under-served disease.Method: Fully human recombinant anti-peanut IgG mAbs were tested in mice sensitized to peanut allergen extract. Allergic mice received intravenous immunotherapy with anti-peanut Ara h 2-specific IgG1 or IgG4 mAbs cocktails, and were then challenged by a systemic injection of high-dose peanut allergen extract. The protection from allergic anaphylaxis was measured by monitoring the core body temperature.Results: PIT with peanut-specific mAbs was associated with a significant and dosedependent reduction of anaphylactic reactions in peanut-sensitized mice challenged with peanut allergen extract. Complete protection was observed at doses approximately 0.3-0.6 mg mAbs. Mixtures of mAbs were more effective than single mAbs, and effective treatment could be obtained with mAbs of both IgG1 and IgG4 subclasses. The therapeutic effect of anti-Ara h 2 mAbs was based on allergen neutralization and independent of the Fcγ receptor and mast-cell inhibition. Conclusion:This is the first report that shows that human-derived anti-peanut mAbs can prevent allergic anaphylaxis in mice. The study demonstrates that neutralizing allergenic epitopes on Ara h 2 by mAbs may represent a promising treatment option in peanut-allergy.

A murine model of peanut-allergic asthma

“…While intranasal sensitisation would more resemble sensitisation in humans (38), we chose the IP route of administration as this has proven to require fewer doses, hence is fast, and since we have successfully used this route for the study of peanut-allergic anaphylaxis with the same allergen extract and for the same strain of mice (24,39). Previous studies with other allergens often use two IP injections for sensitisation.…”

IgG in the control of FcεRI activation: a battle on multiple fronts

“…Two major strategies are currently being employed, both aiming at harnessing the protective role of allergen-specific IgG. Neutralizing monoclonal anti-allergen IgG antibodies have demonstrated efficacy in suppressing allergy in preclinical and clinical settings (64)(65)(66)(67)(68)(69)(70)(71)(72). While the results are generally positive, questions on their cost-effectiveness remain.…”

Potential and limitations of epitope mapping and molecular targeting in Hymenoptera venom allergy

“…It remains open if larger allergens require larger numbers of blocking molecules. Recently, a set of 4 blocking antibodies against Ara h 2 has shown efficacy in animal models, with Ara h 2 being 3-4 times larger than Bet v 1 (94). Food allergens, however, are likely to have different types and numbers of dominant epitopes as compared to venom allergens.…”