Preventing the torrent of signaling molecules that are released during an adverse peanut reaction could not only prove to be helpful to many of the estimated 4.2 million children living with this allergy, but it could also be life-saving to those individuals where the slightest trace of peanut or peanut ingredients could have fatal consequences.
The allergy is the result of allergens binding with an antibody called immunoglobulin E (IgE) on the surface of immune cells, setting off a complex chain reaction that could lead to a response ranging in severity from a rash to anaphylactic shock. Now, investigators from the University of Notre Dame have effectively prevented the binding of peanut allergens with IgE to suppress the allergic reaction to peanuts using the first-in-class design of allergen-specific inhibitors. Findings from the study were published today in PNAS through an article titled “Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen.”
“The success of this study is exciting because it opens the door to establishing an entirely new class of allergy therapeutics,” explained senior study investigator Basar Bilgicer, PhD, associate professor in the department of chemical and biomolecular engineering and affiliate of advanced diagnostics and therapeutics at Notre Dame. “We now have the first functional example of selective IgE inhibition to a food allergen, which we haven’t had before.”
In a process called degranulation, IgE and allergen proteins bind on the surface of immune cells, called mast cells, releasing granules such as histamine, which is the first and most critical step in a patient’s allergic reaction. No current medications exist that are capable of preventing that process. An inhibitor that only targets IgE can lead to widespread immune suppression, which studies have shown can cause an increase in parasitic infection and even cancer.
“Using a nanoparticle-based method, we identified the most crucial binding sites for IgEs on peanut proteins by testing a small population of patient serum with a clinical history of severe allergies to peanuts,” the authors wrote. “We then synthesized inhibitors—we call covalent heterobivalent inhibitors—which specifically and permanently prevent IgEs from binding to peanut proteins and triggering allergic responses.”
For Bilgicer, the challenge was developing an inhibitor that is designed to specifically inhibit the binding of IgE and the allergen proteins without interfering with any other immune system functions. Food allergen-specific inhibitors would stop degranulation, the primary driver of life-threatening allergic reactions, without putting the patients’ immune system or their health at risk.
To achieve their goal, the research team used the nanoallergens to screen and identify the key binding sites on peanut proteins that patient IgE antibodies recognize by studying samples from a small population of patients with severe allergies to peanuts.
“This study presents a design of food allergen-specific sIgE inhibitors named covalent heterobivalent inhibitors (cHBIs) that selectively form covalent bonds to only sIgEs, thereby permanently inhibiting them,” the authors stated. “Using screening reagents termed nanoallergens, we identified two immunodominant epitopes in peanuts that were common in a population of 16 allergic patients. Two cHBIs designed to inhibit only these two epitopes completely abrogated the allergic response in 14 of the 16 patients in an in vitro assay and inhibited basophil activation in an allergic patient ex vivo analysis.”
“The efficacy of the cHBI design has valuable clinical implications for many allergen-specific responses and more broadly for any antibody-based disease,” the study investigators concluded.