Research Alert


Myasthenia gravis (MG) is an autoimmune disease in which a patient’s own immune system generates autoantibodies against proteins in the neuromuscular junction that enable motor neurons to stimulate muscle contraction, and this antibody attack creates weakness that can be life-threatening. A rare subtype of MG occurs when pathogenic B cells generate autoantibodies against a muscle specific kinase called MuSK, and this subtype of MG is particularly severe. Current MG therapy involves generalized immunosuppression, but this leaves patients vulnerable to fatal infection. Investigators at UPenn have created a chimeric autoantibody receptor (CAAR) T cell strategy that targets only the pathogenic B cells that make anti-MuSK antibodies, leaving alone B cells that are directed against other antigens. Ongoing studies are evaluating animal models of anti-MuSK MG to test this CAAR-T approach to use targeted B cell depletion for treatment of MuSK MG. If this strategy is successful, it may open a new and effective way to treat this and other autoimmune diseases of the nervous system.

Full abstract, to be presented at the American Neurological Association 2019 Annual Meeting (October 13-15 in St. Louis):

Antigen-Specific B Cell Depletion for Myasthenia Gravis with Chimeric Autoantibody Receptor (CAAR) T Cells

Sangwook Oh, Ph D. University of Pennsylvania, Philadelphia, PA, USA.

Myasthenia gravis (MG) is an autoimmune disease induced by autoantibodies targeting the neuromuscular junction (NMJ), which can lead to life-threatening muscle weakness. Autoantibodies produced by MG patients destroy the NMJ by fixing complement or disassembling acetylcholine receptor (AChR) clusters. Formation of AChR clusters, which is indispensable for signal transduction via the AChR, depends on activation of the transmembrane protein, muscle-specific kinase (MuSK). Most MG patients exhibit anti-AChR antibodies (85%) or anti-MuSK antibodies (4%). 11% of patients are classified as “seronegative”, which has been attributed to low titer antibodies against AChR, MuSK, or other NMJ proteins. Current therapeutic strategies for MG involve generalized immune suppression to reduce antibody production, which is associated with potentially lethal infections. MuSK MG represents a more severe subtype of disease that has high unmet need for safe and effective therapy. Previously, we showed proof of concept that autoantigen-based chimeric autoantibody receptor (CAAR) T cells can cause potent and targeted B cell depletion in a mouse model of pemphigus vulgaris, a paradigm for human antibody-mediated autoimmune disease. CAAR T cells expand and engraft in vivo, potentially leading to long-term disease remission. To extend the CAAR concept to MG, we generated CAARs expressing MuSK as the extracellular “bait” on the surface of T cells and demonstrate that these CAARs direct T cell cytotoxicity toward cells expressing anti-MuSK B cell receptors. MuSK CAAR T cells activate NFAT signaling and cause specific cytolysis of anti-MuSK target cells, but not cells of other antigenic specificities. To develop an in vivo model for MG, we passively transferred anti-MuSK hybridomas to immunodeficient mice, which resulted in muscle weakness and electromyographic changes characteristic of MG. CAAR T cells represent a novel strategy for targeted B cell depletion in MG, and may ultimately prove to be valuable for the treatment for a broad range of antibody-mediated diseases.

All abstracts from ANA2019 will be available under embargo starting October 4. Contact Katherine Pflaumer ([email protected]) for full meeting abstracts, and for call-in information for the ANA2019 Media Roundtable (Oct. 15, 11 a.m. US Central).

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American Neurological Association Annual Meeting, October 13-15, 2019