Phase 1 Trial of MuSK-CAART Therapy Is Recruiting

Investigational therapy for myasthenia gravis fared well in preclinical study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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MuSK-CAART, an investigational cell-based therapy being developed to treat myasthenia gravis (MG) patients with anti-MuSK antibodies, eliminated disease-driving B-cells in a mouse model of the disease, a study showed.

The findings, some of which were reported previously at a scientific conference, supported Cabaletta Bio’s request for a first in-human trial of the therapy, which the U.S. Food and Drug Administration (FDA) cleared in March 2022.

That Phase 1 trial (NCT05451212) is now recruiting up to 24 adults with MuSK-associated MG at sites in California and Oregon.

“We are hopeful that this precision-medicine approach with CAAR T cells may, if proven to be safe and effective, one day allow for a one-time infusion leading to long-term autoimmune disease remission,” Aimee Payne, MD, PhD, the study’s senior author, said in a press release.

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Payne is a professor of dermatology at the Perelman School of Medicine, University of Pennsylvania (Penn), and director of the Penn Clinical Autoimmunity Center of Excellence. MuSK-CAART was developed in Payne’s laboratory and later licensed to Cabaletta for clinical development.

The study, “Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells,” was published in the journal Nature Biotechnology

MG is caused by self-reactive antibodies that target proteins at the neuromuscular junction — the region where nerves communicate with muscle cells to drive voluntary movement.

Antibodies, including autoreactive ones, are produced by B-cells after a protein on their surface, called a B-cell receptor, binds to the target protein and initiates the process.

In rare cases, MG-driving antibodies target a protein called muscle-specific tyrosine kinase, or MuSK. This form of MG is sometimes associated with faster disease progression and more severe symptoms.


Payne and colleagues developed a cell-based strategy called MuSK Chimeric Autoantibody Receptor T cell therapy, or MuSK CAART, for the treatment of MuSK-MG.

“The new approach we are developing is designed to program the patient’s immune system to kill only the autoimmune B cells that cause disease, while sparing healthy B cells that can protect patients from infection,” Payne said.

The approach was based on the concept of chimeric antigen receptor (CAR) T-cell therapy, which has been approved since 2017 to treat certain types of cancer.

Essentially, CAR T-cell therapy involves removing a person’s immune T-cells and equip them with a lab-made receptor that will specifically recognize a protein on cancer cells, so that they can destroy malignant cells when infused back into the bloodstream.

CAAR T-cell therapy instead modifies patients’ T-cells to equip them with a receptor that will specifically bind to B-cell receptors on MuSK-reactive B-cells. When infused back into a patient’s bloodstream, the therapy is expected to specifically target and kill these autoreactive B-cells.

“We can take T cells, but instead of engineering them to attack cancerous B cells — as in the cancers for which CAR T cell therapy has proven effective — we can engineer them to attack the autoimmune B cells destroying neuromuscular junctions in MuSK-MG,” said Sangwook Oh, PhD, a senior research investigator in Payne’s lab and the study’s first author.

In the  Cabaletta-sponsored study, researchers tested the CAAR T-cell therapy in cell cultures and mouse models of MG.

Tests in cell cultures demonstrated that CAAR T-cells were able to target different parts of the MuSK protein and to kill autoreactive B-cells, while sparing B-cells that don’t produce MuSK antibodies.

Overall, the presence of anti-MuSK antibodies — as would be the case in an MG patient — didn’t compromise the treatment’s ability to kill the cells.

As previously reported, the CAAR T-cell therapy eliminated MuSK-reactive B-cells in mice with a weakened immune system.

Likewise, CAAR T-cell therapy was able to specifically reduce MuSK-reactive B-cells, which comprised less than 2% of antibody-producing B-cells, in a mouse model of MG.

Notably, levels of B-cells non-reactive to MuSK, and overall antibody production, weren’t affected, reflecting the specificity of the treatment to its target cells.

No specific signs of toxicity from the CAAR T-cell therapy were observed.

Broader applications?

Researchers noted that the data informed the design of the Phase 1 clinical trial, but also indicated that CAAR T-cells represent “a platform technology that could be applied to numerous autoimmune and alloimmune B cell-mediated conditions.”

The goal of the Phase 1 trial is to evaluate the therapy’s safety and tolerability across two phases. The first phase will test multiple doses to identify the maximum tolerated dose, which then will be given to patients in the second phase.

MuSK-CAART also has been granted fast-track designation from the FDA, which is intended to help speed its development toward regulatory approval.