Could Dupixent find a new life targeting 'memory' B cells to treat allergies?

Allergies are an inconvenience at best and deadly at worst. But despite around one in three adults and one in four children having seasonal allergies, food allergies or eczema, according to statistics published in January 2023 by the Centers for Disease Control and Prevention, it still isn’t entirely clear how and why they happen. 

A new discovery might offer some answers—as well as open up a potential role for approved biologic drugs like Dupixent or Xolair. In a pair of studies published Feb. 7 in Science Translational Medicine, a team of researchers from Canada's McMaster University and Danish allergy pharma ALK-Abello described a new type of B cell that clings to “memories” of allergies and creates antibodies to them when they’re encountered again. Called type-2 memory B cells, or MBC2s, they appear to have “unique characteristics and a unique gene signature that has not been described before,” one of the study’s co-leads, Josh Koenig, said in a press release

“Let’s say you’re allergic to peanuts. Your immune system, because of MBC2, remembers that you’re allergic to peanuts, and when you encounter them again it creates more of the antibodies that make you allergic,” Koenig said in the release. 

Researchers have long known that IgE antibodies, which stimulate other immune cells called mast cells and basophils, are the key players in the process that ultimately leads to allergy symptoms. But there was one piece of the puzzle they couldn’t explain: Most of the cells that produce IgE antibodies, including B cells, are relatively short-lived, as Science Translational Medicine associate editor Courtney Malo noted in her summary of the new research. If the majority of IgE-producing cells don’t stick around, what might explain chronic allergies? 

To find out, a research team led by Miyo Ota used single-cell RNA sequencing to analyze samples of immune cells taken from 58 children with peanut allergies, along with 14 non-allergic controls. This revealed MBC2s, the volume of which corresponded to higher levels of IgE in the allergic patients. 

In the second study, a team led by Koenig built glowing compounds called tetramers based on molecules in peanuts, birch pollen and dust mites, which they used to isolate antigen-specific memory B cells in immune cell samples taken from adult patients with the allergies, along with a group of non-allergic controls. Single-cell RNA sequencing on these cells again identified the MBC2s, and showed that patients with allergies had higher populations of them than those without.

Additional analysis of patients enrolled in a clinical trial for a sublingual immunotherapy for allergies developed by ALK showed that MBC2s generated IgEs during the first month of therapy, a time when the patients would still be sensitive to the allergen. 

“Identification of [MBC2s] has implications for the development of allergic disease and immunity and is therefore critical in the design of therapeutics in IgE-mediated diseases, including aeroallergies, asthma, and food allergies,” Koenig’s team wrote in their paper. 

The findings suggest that there are two requirements for an allergic reaction, immunologists Anouk von Borstel, Ph.D., Robyn O’Hehir, Ph.D., and Menno van Zelm, Ph.D., who weren’t affiliated with the research, said in a related perspective article published in Science Translational Medicine. The first is the presence of type 2 inflammation—a form of inflammation where the body sends out type 2 immune cells, like mast cells and basophils, in response to intruders—while the second is MBC2s that are specific to a particular antigen. More research will be required to answer additional questions, such as how MBC2 cells are formed, they noted. 

Still, the work already suggests possible avenues for treating allergies. One strategy might be to target MBC2s with biologics, the perspective authors said; a possible contender for the job might be dupilumab, brand name Dupixent, an antibody that blocks receptors found on MBC2s. Another possibility is the antibody omalizumab—Genentech and Novartis’ Xolair—which prevents IgEs from binding to mast cells and basophils, the scientists said. 

“Another therapeutic avenue would be to use allergen immunotherapy in combination with biologicals targeting [a receptor found on MBC2s] or IgE, which could further attenuate type 2 B memory cells and provide a long-term benefit,” they added.