CAAR T-cell Therapy Shows Early Potential for MuSK-linked MG

A new type of immunotherapy successfully eliminated immune B-cells that wrongly target the MuSK protein in people with MuSK-associated myasthenia gravis (MG), a study in mice found.

While the treatment effectively killed damaging B-cells, it spared healthy cells, setting the stage for its possible testing in people. 

The study, “MuSK chimeric autoantibody receptor (CAAR) T cells for antigen-specific cellular immunotherapy of myasthenia gravis,” was presented at the American Academy of Neurology 2020 Science Highlights Virtual Platform. 

MG is caused by the production of autoantibodies against proteins at the neuromuscular junction, the site where nerves communicate with muscle cells. In up to 7.5% of patients, the target is a protein called muscle-specific tyrosine kinase receptor, or MuSK.

Antibodies are produced in B-cells, which have a B-cell receptor (BCR) on the surface. Binding of this receptor to the MuSk protein prompts the formation of the anti-MuSK antibodies that cause MG in this patient group. 

Chimeric AutoAntibody Receptor (CAAR) T cell therapy is an immunotherapy strategy in which immune T-cells are isolated from patients and modified with a harmless virus to produce a unique receptor that selectively binds to B-cell receptors. Modified CAAR T-cells are then returned to the patient to eliminate autoreactive B-cells.

Researchers in the laboratory of Aimee Payne, MD, PhD, a professor at the University of Pennsylvania and co-founder of Cabaletta Bio, in collaboration with Yale Medical School, created CAAR T-cells that specifically bind to the B-cell receptor on the surface of anti-MuSK B-cells. This research was partly funded by Cabaletta, which has an exclusive license to the therapy from University of Pennsylvania.

In vitro tests had shown that CAAR T-cells killed B-cells by targeting different parts of the MuSK protein. Cells that did not generate anti-MuSK receptors remained unaffected, as did proteins normally associated with MuSK. 

To test the therapy in an animal model, mice with a weakened immune system were injected with anti-MuSK B-cells, which were allowed to grow over four days. The animals were then treated with CAAR T-cells. At day 13, results showed the anti-MuSK B-cells were eliminated in treated animals compared with mice given control CAAR T-cells.

Next steps include testing for toxicity along with further work in animal models to support clinical trials, the scientists said. 

Cabaletta’s CAAR T-cell technology has been cleared by the U.S. Food and Drug Administration for clinical studies in people with the rare autoimmune disorder mucosal pemphigus vulgaris. The company plans to begin studies to support an investigational new drug application (IND, a mandatory step to conduct clinical studies) in MuSK-associated MG this year.

“This in vivo data in MuSK-associated myasthenia gravis (MuSK MG), a prototypical B cell-mediated autoimmune disease, is an important step to initiating a comprehensive IND-enabling program,” Payne said in a press release.

“Patients who suffer from MuSK MG have very limited therapeutic options, primarily generalized immunosuppressants, which typically require chronic administration, and can cause significant side effects,” Payne added. “There is a need for a therapy that specifically targets only the B cells causing the disease, while leaving normal B cells unaffected in patients suffering from MuSK MG.”