New discovery could change autoimmune therapy landscape, study suggests

(Press-News.org) Myasthenia gravis (MG) is a chronic autoimmune disorder in which antibodies block communication between nerves and muscle, resulting in weakness of the skeletal muscles. It can cause double vision, difficulty swallowing, and, occasionally, serious breathing difficulties, among other symptoms. Many autoimmune diseases such as MG, as well as a range of other human illnesses, result from the inability to regulate activity of IgG antibodies – collectively, these diseases are referred to as IgG-mediated pathologies.

In a paper out this month in Cell, researchers at Emory University have discovered a family of enzymes that work to reduce IgG-mediated pathologies in diseases like MG. The findings, involving mouse models, show that a specific enzyme (an endoglycosidase called CU43) was particularly effective in treating those diseases caused by overactive antibodies.

“Human antibodies, although critically important for mounting an immune response to pathogens and fighting disease, sometimes cause disease themselves – including autoimmune diseases,” says Eric Sundberg, principal investigator on the study and a biochemistry researcher at Emory University’s School of Medicine. “The enzymes we discovered can modify antibodies in such a way that they no longer cause disease.”

A more effective treatment option

The newly discovered enzyme was used to treat a number of different IgG-mediated pathologies in mice and found to be extremely effective. Compared to drugs currently on the market to treat MG, the new enzyme was found to be much more effective in reducing symptoms, and at a much lower dose – 4,000 times less of the enzyme was needed to create the same biological effect. For patients, a more effective, lower dose could mean less side effects and different options for how the drug is administered.

“The potency of this enzyme is quite remarkable when compared to current treatments for autoimmune diseases and thus warrants consideration for further development for the treatment of this important class of diseases,” says Dr. Jeffrey Ravetch, collaborator and co-author on the paper and immunologist at The Rockefeller University.

“We hope to leverage these promising results in mice to move this enzyme rapidly into clinical trials in humans,” says Sundberg, who also chairs the Department of Biochemistry at Emory. “It could potentially be used to treat a wide range of autoimmune diseases and other IgG-mediated pathologies.”

CITATION: Sastre DE, Bournazos S, Du J, Boder EJ, Edgar JE, Azzam T, Sultana N, Huliciak M, Flowers M, Yoza L, et al. (2024). Potent efficacy of an IgG-specific endoglycosidase against IgG-mediated pathologies. Cell. 187(24). 10.1016/j.cell.2024.09.038

FUNDING: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases grants R01AI149297 (to E.J.S.), R01AI137276 (to S.B.), and U19AI111825 (to J.V.R.) and the National Cancer Institute grant R01CA244327 (to S.B.).

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