An mRNA therapy that aims to train the immune system to tolerate peanut is being tested in its first clinical trial in people.
The treatment, called UKK-0018, starts with a peanut protein that’s redesigned to make it less likely to trigger an allergic reaction. Researchers altered parts of the protein that are recognized by IgE antibodies, which set off allergic reactions.
“UKK-0018 looks like peanut antigen, but many of the IgE binding sites have been blurred out, so there is impaired IgE recognition,” says Dr. Uri Lopatin, CEO of Ukko, the biotech company developing the treatment.
Yet researchers preserved features of the protein that other immune cells still recognize. The hope is that this will help a peanut-allergic individual’s immune system learn to tolerate peanut instead of reacting to it.
How Peanut mRNA Treatment Works
Rather than inject the modified protein itself, Ukko’s therapy uses mRNA. This carries the genetic instructions cells need to make proteins. Once injected, the patient’s cells take up the mRNA and use it to produce the redesigned peanut protein.
The goal is to expose the immune system to a version of the peanut protein that won’t cause an allergic reaction but can still teach the body to tolerate peanut.
Lopatin likens Ukko’s approach to a “reverse vaccine.” A typical vaccine trains the immune system to attack a threat. UKK-0018 instead aims to change the existing allergic response into a protective one.
“Normally you take a vaccine to give you an immune response when you don’t already have one,” Lopatin says. With peanut allergy, “you already have an immune response. We are trying to change the pre-existing pathologic immune response to be a protective response. It’s the reverse.”
Reengineering the Peanut Protein
To build the new peanut protein, Ukko used computational protein design, which combines computer modeling and AI.
Proteins are made of long chains of amino acids that fold into complex shapes. Change one part, and it can change the rest of the protein structure.
So how to alter bits of a protein while keeping other parts intact? Computer models help predict what can be changed to make a protein less allergenic, while maintaining parts that make it recognizable to the immune system, Lopatin says.
With UKK-0018, the scientists altered the epitopes, or sites on the protein that IgE antibodies latch on to. When IgE binds to an allergen, it can trigger a chain of events leading to allergy symptoms including hives, wheezing, swelling, itching, vomiting, diarrhea and, in severe cases, anaphylaxis.
“The hard part is not making a molecule that doesn’t look like its parent molecule,” Lopatin says. “The hard thing is making a molecule that still looks like the parent molecule enough that the immune system will recognize it.”
Once they had engineered the protein, researchers used its genetic sequence to create single-stranded mRNA in the lab. The mRNA is packaged inside a lipid nanoparticle, a tiny protective bubble, that helps deliver it into cells. Inside the body, antigen-presenting cells take up the mRNA and use it to make small amounts of the engineered peanut protein.
The hope is that T cells and B cells will recognize the protein, and steer the immune system toward tolerance. That shift may involve producing protective IgG4 antibodies that help to block allergic reactions.
Lopatin says it may also include changes in cytokines, or signaling molecules, associated with a non-allergic immune response.
‘Compelling’ Mouse Studies
Animal studies have so far been “very compelling,” says Dr. James Baker, director of the Michigan Institute for Atopic Diseases [M-IAD] at the University of Michigan, and a scientific advisor to Ukko.
In research led by his U-M colleague Dr. Jessica O’Konek, highly peanut-allergic mice were given three shots of UKK-0018 or a placebo. She and the team later tried to desensitize the mice to peanut by gradually injecting them with increasing doses of peanut protein.
The mice that received UKK-0018 did not react. However, most of the mice given the placebo injection experienced severe anaphylaxis and died.
Researchers also found changes in the treated mice’s blood biomarkers that suggested their immune systems were responding more like mice without allergy. The mice that received UKK-0018 produced a “beautiful amount” of IgG, Lopatin says.
“They had also changed the nature of their T cell response, so they looked more like non-allergic mice,” he says. There were no adverse events among the treated mice.
When the treated mice’s T cells encountered peanut protein, they produced cytokines associated with immune tolerance.
Baker says the findings suggested researchers had removed the protein’s ability to trigger a reaction without eliminating its ability to stimulate the immune system.
“The immunizations with the modified protein did two things. It shifted the immune response to the peanut protein from a Th2, or allergic type response, to a Th1, which is a protective, suppressive response,” Baker says. “It produces more protective antibody than any other method we have observed.”
T cells may be particularly important for the treatment’s durability, Lopatin says. “The T cells are going to be what’s important for long-lasting immune protection. The animal model gave us hope and now we have to prove that is true in humans.”
Clinical Trial Launches
The Phase 1/2a clinical trial will include up to 40 peanut-allergic adults in Australia and New Zealand. Participants will undergo a food challenge to peanut before the start of the study.
They will receive three injections of UKK-0018. Researchers will test a lower dose and a higher dose, as well as two different intervals between injections. (Lopatin declined to share the intervals.)
The study will primarily measure safety and tolerability. It will also gather preliminary efficacy data. One month after the third shot, participants will undergo a food challenge to determine how much peanut protein they can tolerate. Researchers will also measure blood biomarkers, including peanut-specific IgG4 antibodies.
“This is an early phase study. We hope we have the timing and dose directionally correct, where patients can go up in how much peanut they can tolerate,” Lopatin says.
Researchers will continue to follow some participants for up to 30 weeks. If UKK-0018 works as hoped, peanut tolerance could improve over time.
“Things should get better with time,” he says. “We hope two months will better than one month, and three months will be better than two months.”
Additional treatments or booster shots may not be necessary, he says. “If we successfully retrain the immune system, we may not have to,” Lopatin says. “This is part of why it’s so exciting to us.”
Hope for Other Allergens
Lopatin also points to a potential advantage over vaccines targeting rapidly changing viruses: peanut proteins don’t undergo ongoing evolution. So the therapy would not need to be updated to match new strains.
“Fortunately, peanuts are not evolving,” Lopatin says. “Unlike the flu vaccine or the COVID vaccine which has to be reformulated every year, not just to provide you a boost, but because the thing that is trying to kill you has suddenly changed itself. We don’t have that problem with peanuts. A peanut is pretty happy being a peanut.”
Results from the clinical trial are expected in early 2027. If the approach works, Baker says it could later be expanded to other food allergens, environmental allergens, or insect sting allergies. “The implications are very intriguing but it’s very early on,” he says.
Mouse studies often don’t pan out in humans. “I’ve cured allergies in mice many times,” Baker says. “But they are doing the right thing, trying to take it forward by doing the safety studies.”
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