MuSK-CAART for myasthenia gravis

Last updated Oct. 24, 2024, by Joana Carvalho, PhD
Fact-checked by Inês Martins, PhD

What is MuSK-CAART for myasthenia gravis?

MuSK-CAART is an experimental cell therapy designed to ease disease severity in people with myasthenia gravis (MG) who test positive for antibodies against a protein called muscle-specific kinase (MuSK). The treatment works to lower the number of immune B-cells that specifically produce anti-MuSK antibodies in these patients.

Developed by Cabaletta Bio, the therapy is being tested in a Phase 1 clinical trial as a one-time intravenous, or into-the-vein, infusion.

MuSK-CAART has received fast track status from the U.S. Food and Drug Administration to improve muscle strength and the ability to perform daily activities in people with MuSK-associated myasthenia gravis (MuSK-MG). This designation is given to speed up the development and regulatory review of therapies that address highly unmet medical needs in serious or life-threatening conditions.

Therapy snapshot

How does MuSK-CAART work in myasthenia gravis?

In people with MG, B-cells, a type of immune cell, produce self-reactive antibodies that attack proteins, most commonly acetylcholine receptors (AChRs) and MuSK, that are essential for nerve-muscle communication.

MuSK-CAART is an investigational therapy that’s made to target and eliminate the B-cells that produce autoantibodies against MuSK, while leaving other healthy B-cells unharmed. This may help lower the levels of the harmful autoantibodies that drive MuSK-MG without causing generalized immunosuppression. This approach may enable patients to be symptom-free and remain in remission for long periods of time.

MuSK-CAART is called an autologous chimeric autoantibody receptor (CAAR) T-cell therapy. This means it uses a patient’s own immune T-cells, which have the ability to kill other cells, and genetically modifies them to carry a specialized receptor, called autoantibody receptor or CAAR, that will recognize B-cells producing anti-MuSK antibodies.

The engineered CAAR specifically contains a portion of the MuSK protein, allowing the modified T-cells to attack and destroy MuSK-reactive B-cells once they are infused back into the patient’s body.

The MuSK-CAAR also contains a 4-1BB costimulatory domain and a CD3 zeta signaling domain. Together, these two domains help promote T-cell activation, survival, and persistence, ultimately boosting the ability of the engineered T-cells to successfully attack and destroy MuSK-reactive B-cells.

How will MuSK-CAART be administered in myasthenia gravis?

MuSK-CAART is designed to be administered via a one-time intravenous infusion.

In an ongoing Phase 1 clinical trial involving MuSK-MG patients, a single infusion of the therapy is being tested at various doses with or without a preconditioning chemotherapy regimen, which is generally given to destroy the patient’s immune cells before the modified T-cells are infused back into the body.

MuSK-CAART in myasthenia gravis clinical trials

A Phase 1 clinical trial called MusCAARTes (NCT05451212) is assessing the safety of MuSK-CAART in about 24 MuSK-MG patients with active disease. Participants are being divided into several groups in which a single infusion of MuSK-CAART will be given at different dose levels with or without a prior course of chemotherapy.

The study is testing two different chemotherapy regimens: one made up of cyclophosphamide alone and another consisting of a combination of cyclophosphamide and fludarabine.

This initial dose-finding phase aims to determine the therapy’s maximum tolerated dose, or the highest dose that can be given to patients without causing substantial side effects. It will be followed by an expansion phase, wherein the most promising dosing regimen in the first part will be tested further.

The trial’s main goal is to assess the incidence and severity of side effects, including dose-limiting toxicities, which are side effects that are serious enough to prevent an increase in treatment dosage, and side effects related to MuSK-CAART, over three months. Additional goals include changes in anti-MuSK antibody levels and in several measures of MG severity for up to three years.

MusCAARTes is expected to conclude in 2028.

Common side effects of MuSK-CAART

Clinical testing of MuSK-CAART in people with MuSK-MG is still in the early stages and no results have yet been reported. The therapy’s safety profile in this patient population is still not known.

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