Eating Without Fear
Tad Berkery turned nine years old before he ate his first doughnut.
That’s not because he grew up in a doughnut-free town or because his mother, Stephanie Kuroda, had forbidden him to have junk food up until that point. It’s because, like a growing number of kids in the U.S., Berkery, now 10, grew up with a severe food allergy—his to a traditional doughnut ingredient, egg.
Early in life, it took eating only 0.1% of an egg for Berkery to break out in hives and have difficulty breathing. As a result, he and his family practiced strict avoidance. He sat at a special “food allergies” table in the school lunchroom. He brought his own cake to friends’ birthday parties. And he abstained from now-beloved foods like pastas and dips.
After he turned six, though, his allergist, Robert A. Wood, invited him to participate in a study under way at Johns Hopkins Children’s Center, in Baltimore. The aim of the experiment, called oral immunotherapy, was to help Berkery and other young participants build tolerance for egg by eating tiny, but progressively increasing, doses. The ultimate goal was to rewire the kids’ immune systems so the children no longer had to live in fear of accidentally ingesting the dreaded egg.
“I hemmed and hawed about joining the trial for a long time,” Kuroda recalls. “As a parent, you sit there and wonder, ‘Is it going to work? What if it makes things worse?’ ”
Berkery was more certain. “I said I think we should try it,” he remembers. He told his parents, “It might get rid of my egg allergy, and Dr. Wood has never let us down before.”
Their decision to sign up for the study paid off. By the time Berkery was nine, after a little more than two years of drinking egg-protein powder in his orange juice every day, he was able to eat 10 g of the stuff without having an adverse reaction—that’s the equivalent of eating one large egg. The day Berkery aced the 10-g test, conducted at Johns Hopkins, was the Day of the Doughnut.
“Right after he passed the challenge, I asked him what he wanted to eat to celebrate,” Kuroda says. “I thought he would say cake or ice cream.” But Berkery wanted to go somewhere exotic: Dunkin’ Donuts.
Today, allergists across the country view oral immunotherapy as the most promising, near-term way to help food-allergy sufferers. Clinical trials are ongoing, not just for egg, but also for other allergy-triggering foods such as milk and peanuts. Initial results are promising. But the therapy is time-consuming and risky for patients, and if eventually approved for use by allergists, it would be costly because of frequent trips to the doctor’s office. It also doesn’t work for everyone. For instance, only 75% of the original participants in Berkery’s study made it to and passed the 10-g egg challenge (N. Engl. J. Med., DOI: 10.1056/nejmoa1200435).
So researchers are developing and testing alternative therapies for food allergies, which now affect one out of every 13 children in the U.S. under age 18. The scientists are targeting the molecular and cellular pathways responsible for allergic reactions, hoping to eventually offer those with food allergies more elegant, less labor-intensive treatments than immunotherapy.
“Currently, there is no cure for food allergies,” says Mary Jane Marchisotto, executive director of the Food Allergy Initiative, a nonprofit organization that funds allergy research and educational programs. Drugs currently on the market—such as antihistamines, epinephrine, and corticosteroids—are administered only after someone is exposed to an allergen and has an anaphylactic reaction, she explains. “To date, there’s nothing available to prevent the reaction from happening in the first place.”
Although Berkery never ended up in the hospital because of an adverse reaction to egg, the same cannot be said for many of the other 15 million Americans with food allergies. Try as they might, food-allergy sufferers sometimes can’t avoid exposure to allergens at restaurants or in mislabeled products (see page 18). “Mainly because of accidental exposure, food allergies send an American to the emergency room, on average, every three minutes,” Marchisotto says.
Not only are these visits traumatic to patients, they are also an economic burden. According to a study in the Journal of Allergy & Clinical Immunology, reactions caused by food and anaphylaxis cost the U.S. about $500 million in 2007 (DOI: 10.1016/j.jaci.2011.03.013).
Although the concept of having “allergies”—hypersensitivities to typically innocuous foods or particles—has been around since the early 1900s, it wasn’t until the 1960s that researchers started to have an inkling of the molecular basis of the disease. That’s when the antibody immunoglobulin E (IgE) was characterized.
IgE is the ringmaster at the center of the circus that is allergy immunology. Every person’s body produces a certain base level of the Y-shaped macromolecule. But when an allergen—usually a protein from a food or from pollen—gets inside the body, the immune system synthesizes specialized IgE that recognizes the allergen.
All of the other cells and molecules involved in the allergic response, however, are the same from person to person, says Wood, who, aside from being Berkery’s doctor, is the director of allergy and immunology at Johns Hopkins Children’s Center. So food-allergy, hay fever, and asthma sufferers’ symptoms all get triggered by the same molecular pathways, he says. “There might be a different set of symptoms for each person, but that’s more likely related to the dose of the allergen and the route of delivery than it is anything different in the underlying mechanism,” he adds.
The first time a person gets exposed to an allergen is called sensitization. During this phase, the offending protein sticks to generic IgE that decorates the outside of immune cells such as dendritic or mast cells. These cells hang around anywhere that tissue contacts elements from the outside world—in skin and in the mucosal lining of the nose, throat, stomach, and intestines.
This interaction triggers other immune cells, called T cells, to release interleukins, which are signaling molecules that, in turn, command B cells to start pumping out allergen-specific forms of IgE. This new IgE then makes its way to mast cells and white blood cells called basophils, coating their outsides and lying in wait for the next time the allergen comes along.
When that happens, the allergen forms a complex with a couple of IgE antibodies stuck to the cells. That complex triggers the release of histamine, leukotrienes, and a slew of other molecules that jump-start inflammatory responses such as runny noses, itching, swelling, diarrhea, and even vomiting.
“What’s remarkable about IgE is that it can elicit such a powerful reaction,” says Brian J. Sutton, a chemist and biophysicist at King’s College London. Because IgE is sitting there, already bound to the mast cells and basophils, when an allergen is introduced, the allergic reaction is immediate and explosive, he explains.
Contrast this with the body’s immune response to bacteria and viruses, a different pathway mediated by a different antibody, immunoglobulin G (IgG). If you catch a flu virus, Sutton points out, it takes a few days to build up IgG, and then you gradually get a fever.
As a result of its central, potent role in the immune system, IgE is considered by many to be a prime drug target for treating allergies of all kinds.
One treatment aimed at IgE that’s already commercially available is omalizumab. Comarketed by Genentech and Novartis under the brand name Xolair, this therapeutic is a monoclonal antibody designed to mop up free IgE in a person’s body.
“An ordinary antibody to IgE could kill people,” says Tse Wen Chang, originator of the anti-IgE concept and a distinguished research fellow at Academia Sinica, in Taiwan. That’s because if the antibody stuck to IgEs that were already bound to mast cells and basophils, the interaction might trigger anaphylaxis via histamine and those other inflammatory compounds.
“So you can imagine that when I approached people initially with the idea, they were very concerned,” Chang says. This was in 1989, soon after Chang had cofounded a small biopharmaceutical firm called Tanox. He was looking for a corporate partner to fund the company’s anti-IgE program.
Chang eventually convinced Tanox’ potential partners and others in the immunology field that his IgE antibodies were safe. He demonstrated that the therapeutics, screened and selected during synthesis, bind free IgE and not mast-cell-bound IgE. After a partnership with Novartis, a few infamous legal disputes with Genentech, some clinical trials, and an eventual buyout by Genentech in 2007, Tanox disappeared from the pharma scene.
But the anti-IgE concept, in the form of Xolair, has lived on. The monoclonal antibody was approved in 2003 by the Food & Drug Administration for use in patients with moderate to severe persistent cases of asthma. The injectable therapeutic is now involved in more than 100 clinical trials for various types of allergies, including for the treatment of chronic hives and eczema.
Xolair hasn’t made as much headway, though, in treating food allergies, Chang says. A small study, published last year, aimed to test whether peanut-allergy sufferers could benefit from regular injections of the antibody (J. Allergy Clin. Immunol., DOI: 10.1016/j.jaci.2011.01.051). But the trial was discontinued because a few patients had severe anaphylactic reactions to test-doses of peanuts—given to them prior to Xolair—and a safety committee deemed the experiment too risky.
The results, however, looked positive for the few who completed treatment before the plug was pulled: Patients receiving Xolair had significant decreases in their blood IgE levels and, on average, could tolerate more peanut protein than those receiving the placebo.
So food allergists haven’t given up on Xolair. Instead of being used by itself, the antibody is now being administered in combination with oral immunotherapy: Phase I and Phase II trials are under way to see whether the therapeutic can improve the outcome of milk- and peanut-allergy treatments.
Once its patent expires in 2017, the price of Xolair—which is about $8,000 to $20,000 per year—will come down, Chang says. So if the drug passes muster in some of these trials, patients may eventually receive it for their food allergies.
Even so, Sutton says, the anti-IgE therapy doesn’t work for everyone. “If you’re a bigger person and you’ve got a relatively high base level of IgE in your body, you may not qualify for the drug,” he explains. Because of dosing restrictions, doctors simply cannot inject enough Xolair into the body to mop up all of the free IgE.
To address these problems, both Sutton and Chang are looking into other strategies.
Around 1990, Chang also came up with the idea to target antibodies, not at free IgE in the body, but at a version of IgE nestled in the membranes of B cells. These cells are the very same ones that synthesize allergen-specific IgE.
“If you inhibit these B cells,” Chang explains, “the IgE pathway is really cut off.” The strategy also has the potential advantage of requiring less antibody, and therefore less frequent injections, than the anti-IgE therapy, so a person’s size and free IgE levels don’t matter. “If you inhibit B cells,” Chang explains, they don’t regenerate quickly and the pathway is “dead” for a few months.
Genentech is also pursuing a version of this type of antibody, recently dubbed quilizumab. The firm is not yet testing it on food-allergy sufferers, but it is currently in trials for asthma.
Sutton, on the other hand, is focused on IgE-targeted small-molecule drugs, which could be taken orally and would theoretically cost less than injectable antibodies. Others have tried this approach before and failed, he says, but that’s because they were attempting to directly block IgE from binding to its receptor, called FcεRI, on mast cells and basophils. IgE and its receptor interact over a very large surface area, Sutton explains. “And IgE binds its receptor three orders of magnitude tighter than any other antibody binds to its receptor.”
A small molecule could never directly block that strong of an interaction, Sutton argues. The chemist does think, however, that a small molecule could bind to IgE and allosterically lock it into a conformation that won’t stick to FcεRI.
Last year, Sutton, Hannah J. Gould, and coworkers at King’s College finally got a closer look at the antibody-receptor interaction when they solved the X-ray crystal structure of IgE’s stem region bound to the extracellular portion of its receptor (Nat. Struct. Mol. Biol., DOI: 10.1038/nsmb.2044). The stem of the Y-shaped macromolecule is the part that binds to FcεRI, leaving its arms to interface with allergens.
Earlier, in 2002, the researchers had found that, by itself, IgE is bent—its arms bend backward because of a kink, or hinge, in the macromolecule’s stem (Nat. Immunol., DOI: 10.1038/ni811). The new antibody-receptor structure revealed that when IgE’s stem binds to the receptor, the bend becomes even more pronounced. So Sutton’s strategy for a small-molecule therapeutic has been to find compounds that stick to IgE and force the antibody into a conformation that prevents receptor binding.
IgE is like a door slamming into its frame (the receptor), Sutton explains. “It’s a tight fit, so to close the door, you’ve got to change the structure of the hinge a bit.” To prevent the door from closing, he adds, “you can put a wedge, or small molecule, in the hinge.”
Sutton says he and the rest of the team have come up with some hit compounds that stick to IgE in this way by running screening assays. But they aren’t yet ready to disclose the structures. The researchers first want to determine precisely where the small molecules bind to IgE.
Not all pharmacological allergy research is focused on IgE, however. Some scientists are targeting interleukins, the signaling compounds that tell B cells to start pumping out IgE, and others think that blocking T cells is the way to go. Still others believe that allergies are too complex to be stopped via one molecular target.
“There’s so much redundancy in the pathways that lead to the disease,” says A. Wesley Burks, president of the American Academy of Allergy, Asthma & Immunology. A successful therapeutic “would have to target multiple pathways, and that’s hard to do.”
In addition, some allergy researchers argue that putting a patient on a single-target drug like Xolair is just a temporary fix. “We don’t yet know the long-term impact of Xolair on tolerance,” says Wayne G. Shreffler, the director of the Food Allergy Center at Massachusetts General Hospital. “There’s no data to suggest that as soon as you stopped taking it, things wouldn’t go back to default.”
Oral immunotherapy, on the other hand, “has an opportunity to modify the disease,” says Burks, who is also the head of pediatric allergy and immunology at the University of North Carolina School of Medicine. And researchers have observed some signs that the treatment does, in fact, alter patients’ immune systems. They’ve seen IgG levels increase and IgE levels decrease (after a brief, initial boost) in immunotherapy participants. They’ve also noticed that mast cells and basophils become less reactive.
But the researchers are far from understanding why some patients become tolerant and others don’t.
In the case of Berkery’s egg therapy, only a handful of the original participants seemed to achieve true tolerance to egg by the end of their treatment. After the 10-g egg-protein challenge, the kids stopped eating egg for four to six weeks and then returned to the research center for a final test.
Only 28% of them were still able to ingest large amounts of egg without reacting. Unfortunately, Berkery was among those who failed. After almost two years of treatment, the youngster lost some of his tolerance in just a matter of weeks. “So it seems Tad needs to keep some base level of egg in his diet to maintain his defenses,” Kuroda explains. He does this today by eating egg in his meals at least twice a week.
Experts in the field are hopeful that longer periods of oral immunotherapy—three, four, or five years rather than two—might modify the disease for a greater segment of patients. They’re collecting data now and gearing up for larger Phase III trials to test the hypothesis. Wood, Berkery’s allergist, is hopeful that if all goes well, the treatment might be available to the general public in eight to 10 years.
“But even though studies haven’t yet determined whether people overwhelmingly get cured with oral immunotherapy,” says Scott H. Sicherer, a researcher in the Jaffe Food Allergy Institute at Mount Sinai Hospital, in New York City, “many people, especially parents, are satisfied with an increase in threshold to an allergen because it adds a safety barrier.”
Berkery agrees. “I would recommend this to others,” he says. “It might not work completely, but if it does anything, you’re safer than you were.” But don’t try this at home, Kuroda warns. “If you have a reaction, you want access to medical care.” She and Berkery were required to trek from Herndon, Va., to Johns Hopkins every other week, when his egg-protein dose was increased so that doctors could keep an eye on him.
As scientific progress marches on, and scientists learn more about how tolerance works in the immune system, better strategies for treating food allergies will no doubt emerge, says Marchisotto of the Food Allergy Initiative. “We don’t yet know what the best solution is,” she says. At the moment, “we’re focused on finding the best solution for right now.”
And right now, Berkery is happy to report that he’s sampled enough doughnuts in the past year to have a favorite: a fresh-baked, still-hot, glazed Krispy Kreme.