As with other food allergies, people who are severely allergic to peanuts have few good ways to protect themselves—apart from total avoidance. While using oral immunotherapy to desensitize oneself to peanuts is an option for some, the purported flop of Aimmune’s Palforzia suggests that patients and clinicians aren’t nuts about the commitment or appetite for risk required to make it work.
Enter a new compound from researchers at the Indiana University School of Medicine. In a paper published in Science Translational Medicine on Feb. 9, the scientists described how they used a covalent heterobivalent inhibitor, or cHBI, to prevent peanut-specific anaphylaxis in mouse models. The drug held off anaphylaxis for at least two weeks in the mice after a single dose without any obvious signs of toxicity.
“These new findings suggest that cHBI has the potential to be an effective preventative for peanut-specific allergic responses in patients,” co-senior author Basar Bilgicer, Ph.D., said in a press release.
There are four known types of allergies, aptly named Types I, II, III and IV. Food allergies fall under Type I, meaning the molecule that causes symptoms is a protein called an IgE antibody. When an IgE antibody recognizes an antigen, it latches onto a tiny portion of it known as an epitope. The antibody then binds to a mast cell, a type of immune cell.
In response, the mast cell undergoes a process called degranulation, releasing a swarm of proteins that call other immune cells in to battle to fight off the “invader.” In a frenzy to help the immune cells get there faster, the proteins dilate and permeate blood vessels all over the body. This causes the blood pressure to drop suddenly, depriving the brain, heart and other organs of oxygen. The drug epinephrine can reverse anaphylaxis by constricting blood vessels, but if not treated quickly, the host can die from anaphylactic shock.
The drug developed by the Indiana University team prevents anaphylaxis by permanently binding to the allergen binding sites on IgE antibodies that are specific to peanut proteins. The team had previously shown that it works in cells, and in their latest study sought to validate their findings in animal models.
But first, they needed to build one. They “humanized” mice by engrafting them with mast cells grown from human stem cells, then induced anaphylaxis by priming the mice with a cocktail of peanut-specific IgE antibodies before exposing them to peanut allergens via an intravenous injection. Afterward, to ensure that the implanted human mast cells had undergone degranulation, they measured serum levels of the protein tryptase, a biomarker used clinically to confirm anaphylactic reactions in patients. The researchers repeated this process for each group of mice in their experiments.
The team first set out to learn whether cHBI could prevent anaphylaxis if the mice were exposed to the allergen shortly after the drug was administered. They dosed one group of mice with cHBI via IV 24 hours after sensitizing them to peanut proteins, dosing a second group with a saline solution as a control. One hour later, they injected them with the allergen.
While the mice in the control group showed symptoms of anaphylaxis—as measured by a drop in core body temperature—the mice in the cHBI group did not. Their serum tryptase levels barely budged above baseline, according to figures in the paper, while the levels in control mice increased as would be expected with an anaphylactic reaction.
The next set of experiments measured how long the protection against anaphylaxis endured. After being sensitized and dosed intravenously with either cHBI or saline, the mice were exposed to the allergen again via injection at four different periods: one, four, seven and 14 days after administration. The mice in the treatment group had no reaction to the allergen throughout the first three challenges, while body temperature of the mice in the control group dropped. The experimental mice’s tolerance held up at the two-week mark, though their serum tryptase concentrations rose slightly.
While the mice did see a drop in protection in expanded duration studies that challenged them with the allergen at four and six weeks, the scientists wrote that overall, “our data demonstrate that cHBI is protective for an extended period of time.”
The next set of studies measured how well the drug could treat anaphylaxis after it had already begun. Sensitized mice were injected with peanut proteins, then injected with cHBI or saline around two minutes later—about the same amount of time it would take a patient to begin feeling an oncoming anaphylactic reaction. The body temperature of the control mice dropped, but the ones that received cHBI were protected. As in earlier experiments, their tryptase levels were lower, too.
Finally, the researchers examined whether their drug could prevent anaphylaxis in the case of an oral exposure. One hour after injecting the sensitized mice with either cHBI or saline, they gave them by mouth the equivalent of four peanuts in a human patient—more than an accidental exposure, but less than what allergists give patients when they’re testing them in a food challenge. The control mice became anaphylactic, and six of them died. On the other hand, all the experimental mice survived without any reaction. Administering the drug two minutes after an oral exposure gave roughly the same results, with only slight body temperature dips and mast cell activation in the experimental mice.
“The ability of CHBI to block the release of mast cell mediators in [mouse models] suggests similar protective effects in peanut-allergic individuals after accidental peanut exposure,” the scientists concluded.
The work is not without limits. First, the researchers noted in the study that the duration challenges were hampered by the fact that the engrafted IgE antibodies were not replenished in the mice over time, causing them to become less sensitive to the allergen. After one week, the scientists needed to give them higher doses of allergen to trigger anaphylaxis. On top of that, mast cells aren’t the only cells at play in IgE-mediated anaphylaxis1: T-cell and B-cell responses can also contribute to allergic reactions and couldn’t be studied in the mouse model, the scientists noted.
Still, the results make a case for trying the approach in humans, the scientists said. They also believe the same drug design could be applied to other food allergens and even to other autoimmune conditions.