Therapy Aims to Turn IgE Allergy Antibodies into Reaction Blockers

A biotech company has developed a technique that transforms the antibodies that trigger allergic reactions into reaction blockers. Their first clinical trial on adults and teens with peanut allergy is set to begin in late 2024.

The innovative method developed by California startup IgGenix relies first on identifying the B cells in the blood that produce IgE antibodies. IgE is the major culprit in allergic reactions, but challenging to isolate.

When you have a food allergy, IgE antibodies to that food trigger become attached to cells called mast cells and basophils. If you consume that allergen, the IgE latches onto it. This triggers the mast cells and basophils to spew out histamines and other inflammatory chemicals that lead to symptoms such as itch, hives, swelling and potentially anaphylaxis.

To prevent this, researchers isolated the IgE and snipped off a portion of it. They then replaced that portion with a segment that transforms the IgE into a different type of antibody – IgG4. IgG4 is a protective antibody. It blocks the IgE from binding with the allergen – and triggering mast cells and basophils to release chemical agents.

“We’re able to chop off the part of the IgE antibody that binds to the mast cells and basophils, called the Fc portion, and instead we put on a benign portion that doesn’t bind,” says Dr. Jessica Grossman. The CEO of IgGenix explains that the new antibody “binds to peanut, but it no longer binds to the mast cells or basophils.”

The antibody for peanut, dubbed IGNX001, has already shown success in peanut-allergic mice. After a single injection of IGNX001, the mice didn’t react during an oral food challenge to peanut. Blood tests found their mast cells and basophils were no longer triggered when exposed peanut protein.

IgE Therapy: Goal of Many Allergens

Although peanut allergy is the company’s first treatment target, the approach should work for many allergens, says Derek Croote, PhD, IgGenix’s chief technical officer. The research team is working on creating batches of their monoclonal (lab-created) IgG4 antibodies for other major food allergens. They’re also investigating the therapy with allergens for dust mites, cat, dog, pollen and alpha-gal syndrome.

Ultimately, Croote says, they plan to build “a comprehensive database of IgE antibodies specific to everything humans are allergic to.”

IgGenix was founded by Dr. Kari Nadeau, Dr. Stephen Quake and Croote based on research they worked on at Stanford University. Nadeau is the former director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford University and is now at Harvard University. Quake is a Stanford professor of bioengineering and applied physics, and co-president of the Chan Zuckerberg Biohub. Croote’s expertise is also in bioengineering.

To develop the treatment, the research team first had to overcome a challenge – finding and isolating the B cells that produce IgE antibodies. This “is our secret sauce,” Grossman says of IgGenix’s patented process.

Re-engineering IgE into IgG4   

B cells are a type of white blood cell. Only a tiny fraction of them actually produce IgE – less than 10 for very every 10 million white blood cells. “IgE antibodies are rare, and the blood cells that make them are rare,” Grossman explains.

A breakthrough came in 2018, when Croote and colleagues isolated single IgE-producing B cells from six patients with peanut allergy. Of 973 suspect B cells, their investigation confirmed 89 “were actually the truly rare cells I was after,” Croote says.

Further study revealed that IgE antibodies bind to peanut protein in a similar place, called an epitope, from person to person. “It turns out that many people’s IgE is directed against the same spots on the same peanut allergen. That led us to an understanding that, if we block IgE from binding these spots, we can … prevent allergic reactions,” Croote says.

As a next step, researchers altered the IgE so that it would no longer latch onto the allergenic protein, mast cells and basophils. IgE antibodies are shaped like a Y. They cut off the bottom portion of the Y and replaced it with a different segment. That transformed it into an IgG4 antibody. The IgG4 antibody binds with the peanut allergen, while leaving the mast cells and basophils alone.

While a patient would still have existing IgE primed to grab onto the allergen, it won’t get the chance to. Croote says circulating IGNX001 antibodies “will intercept allergenic peanut proteins” first. As happened with the mice, this prevents the IgE binding that triggers symptoms.

IgE Therapy: Shellfish, Cat Possible

Croote and his IgGenix team have now analyzed blood samples from over 200 patients with a range of allergies. They’ve isolated some 10,000 IgE antibodies to numerous foods, cat, dog, dust mites, pollen, and alpha-gal.

They’re in the process of making batches of IgG4 for additional allergens. This involves sequencing the DNA and cloning the cells, so that they can be reproduced in large numbers. Shellfish will likely be next up, Grossman says. Other allergens will follow.

For some allergens, one protein is behind the allergic reactions. Therefore, blocking only one “immunodominant” protein should be enough to halt reactions, Croote says. This seems to be the case with peanut, and also potentially cat allergy, in which the protein Fel d1 is mainly to blame for the sneezing or wheezing. However, some allergens, like milk, may require blocking more than one allergenic protein to provide protection.

Croote says they looked for patients with severe allergies, and their powerfully binding IgE. Called “high affinity,” this is IgE that “the moment it sees and allergen, it grabs onto it, and doesn’t let go,” Croote says.

“We choose blood samples from people with extremely severe forms of disease because that is beneficial to our therapeutic process,” Croote says. “What better a starting point for a blocking therapy than an IgE that causes such potent reactions to an allergen?”

Clinical Trial to Kick Off

The first clinical trial for IGNX001 will enroll 24 peanut-allergic patients ages 15 and older in Australia. Study participants will undergo a food challenge to peanut prior to receiving a single injection of IGNX001.

“I am absolutely thrilled to be moving into human trials with a therapeutic for food allergy. This is a dream come true,” Croote says.

Since it’s a Phase 1 study, the researchers are primarily looking at the safety and tolerability of two dosing levels. But participants will be followed for three months to see how long the antibody remains in the blood and at what concentration.

Studies in primates suggest the dosing interval could potentially be an injection every other month, or six times a year. Each shot would cover one allergen, so if you have multiple allergies, you’d need an injection for each one. To maintain protection, the treatment would likely need to continue indefinitely, Croote adds.

Participants in the controlled trial will undergo skin and other tests and, at one month, an oral food challenge.

Grossman says the treatment has a similar effect as oral immunotherapy – only it would work much faster. In OIT, allergic individuals eat small amounts of their food allergen in increasing doses over the course of several months to build tolerance.

One effect of OIT is that levels of IgG4 often rise over months or years. With the IgGenix monoclonal antibody treatment, Grossman says “instead of having to wait for your body to naturally drive up levels of IgG, we’re going to give it to you in a shot. It’s giving you all of that protection from OIT, in a single shot.”

IgE Therapy: Fast Protection

Croote adds that OIT can also have side effects and safety concerns due to patients having to consume the allergen doses.

“Why put patients through this long, often challenging course of treatment where on a daily basis they’re exposed to what they’re allergic to in order to generate these IgG4s? Why not just give them the best most protective IgG4s in a subcutaneous injection and have them protected almost immediately?” he says.

As with Palforzia and Xolair, the two food allergy treatments approved by the U.S. Food and Drug Administration, Croote anticipates that an IgGenix product label would also recommend continued food avoidance.

However, research in animals suggests patients may be able to tolerate substantial amounts of their allergen. He says they’ll learn more about protection levels in the clinical trials.

If it gets approved, Croote says the IgGenix treatment could begin working in a few days. “We think that will be revolutionary for patients and caregivers. Imagine your kid going to summer camp and having them injected with a shot just a week beforehand, which would significantly reduce that anxiety” around camp.

“We think those types of scenarios will really bring the advantages of our product to light,” he says.

For Croote, the quest to develop a better allergy treatment has a personal element. He has a severe milk allergy that has sent him to the ER on multiple occasions. While traveling in France in June, he had a reaction while eating out. The reaction occurred despite his being “very careful,” and being assured by restaurant staff that his meal was dairy-free. His symptoms resolved after using his epinephrine auto-injector.

“I am all too familiar with the symptoms of an allergic reaction and the need for there to be better treatments,” Croote says.

Source: https://www.allergicliving.com/2024/06/24/therapy-aims-to-turn-ige-allergy-antibodies-into-reaction-blockers/

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