Derek Croote has never eaten pizza, ice cream or milk chocolate; he has a lifelong dairy allergy. He’s one of more than 200 million people worldwide who have food allergies. That’s why, when he came to Stanford University in 2013 to join Stephen Quake’s lab, Croote was thrilled to apply the group’s single-cell technology to a longstanding challenge in allergy research: isolating immunoglobulin E (IgE)-producing B cells. It’s been known for decades that IgE mediates allergic reactions, but neither the cells that produce these antibodies nor the individual antibodies had ever been isolated.
Allergic reactions erupt when mast cells spew out histamine and other inflammatory chemicals that cause itching, hives and potentially life-threatening anaphylaxis. Food allergy therapies aim to prevent this inflammatory release, which is triggered when IgE binds food allergens and docks onto surface receptors of histamine-containing cells.
At present, people with food allergies have limited treatment options. Beyond avoiding culprit foods and carrying epinephrine to stop emergency reactions, some get allergen immunotherapy—a regimen that uses escalating, daily doses of the food to desensitize the immune system over time. In January 2020, the US Food and Drug Administration approved standardized peanut flour capsules (Aimmune Therapeutics’ Palforzia) as a therapy for children with peanut allergies; the European Medicines Agency followed with an approval several months later. A few allergists offer unregulated immunotherapy using commercial peanut powder and other food flours. However, allergic reactions are a common side effect of these repeated food exposures, making both routes infeasible for many patients—including Croote.
Studies of the immune system’s allergy arm are complicated by the rarity of IgE-producing B cells. They’re outnumbered a million to one by other blood cells, and IgE represents just 0.005% of serum proteins. Yet IgE is exceedingly potent, says physician-researcher Kari Nadeau, who directs the Sean N. Parker Center for Allergy and Asthma Research at Stanford University. For allergies, IgE “is the match that lights the fire,” she says.
Quake’s lab approached this by analyzing blood from patients under Nadeau’s care for food allergies, to isolate the actual cells that produce high-affinity, specific IgE to food allergens. Croote used fluorescence-activated cell sorting to capture single B cells with surface IgE, then determined each cell’s isotype post hoc using single-cell RNA-seq to read the immunoglobulin heavy chain sequence. Post hoc isotype assignment allowed them to sacrifice specificity and capture IgE B cells with high sensitivity without complex gating schemes, as described in a 2018 Science paper. In total, they analyzed 973 B cells from six allergy patients, of which 89 produced IgE.
On the basis of the similarity of variable gene sequences in the antibodies’ antigen-binding region, the researchers clustered the cells into clonal families. Curiously, multiple individuals harbored the same clonal family with high affinity to multiple allergenic peanut epitopes—suggesting it should be possible to create a broadly applicable therapy using IgEs from a limited number of people with allergies.
For such people, B cells can be a double-edged sword. Besides producing allergy-triggering IgE antibodies, they also make inhibitory IgG antibodies that snuff out the fire lit by IgE. In fact, one person in Croote’s study had IgG4 antibodies that competed for the same peanut epitope as that person’s IgE. (Immunoglobulin isotypes’ different Fc regions produce different functional outcomes.)
During desensitization immunotherapy, regular dosing with the culprit food triggers allergen-specific IgG levels to rise. Over time, enough IgG can be produced to bind up the allergens before they encounter the rarer IgE antibodies. But without regular exposure to the allergen, the B cells quit making IgG—so immunotherapy patients who stop dosing can lose that protection, Nadeau says.
Puzzling over these issues on a phone call with Croote and Quake in summer 2018, Nadeau recalls an ‘aha’ moment. “I remember Steve saying, ‘Yeah, but wouldn’t it be cool to clip out the [IgE] tail and put in the IgG tail,’” she says, “and boom, now you’ve got an inhibitory molecule.”
And thus IgGenix was launched in late 2019, with Nadeau and Quake as scientific co-founders and Croote as chief technical officer. The goal is to develop therapeutic monoclonal antibodies (mAbs) that could be given as monthly shots to tame allergic responses to specific foods. The company came out of stealth mode last August with a $10 million series A investment led by Khosla Ventures and Parker Ventures. Jessica Grossman, a physician by training with leadership experience at several biopharmaceutical companies, is the helm.
Besides being passionate about empowering women—fewer than 3% of venture-funded companies are women-led—Grossman was drawn to IgGenix because food allergy treatments transform not just the lives of patients, but also their families. “And who’s the chief medical officer of the family?” she says. “Well, it’s Mom.”
IgGenix isn’t the first to develop a food-allergy biologic. Two mAbs have supplemental indication approvals for food allergy: Xolair (omalizumab), an anti-IgE humanized IgG1 mAb developed by Genentech and Novartis; and Dupixent (dupilumab), a human IgG4 mAb from Regeneron and Sanofi that binds to the interleukin-4 receptor α subunit. These were originally approved for severe asthma and eczema, respectively. IgGenix would be the first company to develop a mAb treatment designed specifically for food allergy.
The same year Croote and colleagues published their isolation of IgE-producing B cells from patients allergic to peanuts, Regeneron scientists reported developing fully human IgG4 mAbs that reduce allergy symptoms in mice and patients allergic to cats. The two approaches are conceptually similar—both harness the immune system’s natural production of IgG to compete with IgE antibodies—but each goes about it differently. Whereas Regeneron generates IgG4 mAbs by immunizing transgenic mice containing the human immune genes, IgGenix engineers antibodies based on molecules isolated directly from patients with severe allergies. “We feel that the best approach to blocking severe reactions in humans is by starting with the very molecules that are causing those reactions in the first place,” Croote says.
This is important because IgE antibodies bind very strongly to allergens. Using patient IgE as starting material before swapping in an IgG tail, the portion of the engineered antibodies that sees the allergen remains very high affinity, says Cecilia Berin, who studies the immune basis of food allergies at Mount Sinai’s Icahn School of Medicine.
IgGenix’s antibodies, unlike immunotherapy regimens, are meant to prevent allergic reactions but would not retrain an individual’s immune response. Patients “would always be allergic and would always be treated for that allergy,” Berin says. So the company’s antibodies “would likely be an expensive therapy that may have to be given for life.”
So far, the IgGenix team has generated batches of engineered human IgG mAbs to peanut, cashew, walnut, shellfish and milk. The researchers plan to pick a lead candidate, start manufacturing it and be in phase 1 in about 18 months, according to Grossman.
And though the company is starting with food allergy, “It doesn’t end there,” she says. IgGenix’s technology can be used to isolate and re-engineer IgE mAbs as therapeutics to treat allergies to dust mite, latex and medications, as well as in a host of allergic diseases.
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