Targeting NMDAR encephalitis with Chimeric AutoAntibody Receptor T cell therapy (CAAR-T)
Dr Harald Prüß, DZNE - Deutsches Zentrum für Neurodegenerative Erkrankungen in der Helmholtz-Gemeinschaft; Dr S. Momsen Reincke, DZNE - Deutsches Zentrum für Neurodegenerative Erkrankungen in der Helmholtz-Gemeinschaft; Dr Inan Edes, Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft
Anti-NMDA receptor (NMDAR) encephalitis is the most common autoimmune encephalitis causing psychosis, seizures and cognitive impairment. Pathogenic autoantibodies against the NR1 subunit cause receptor internalization and clinical symptoms. Current treatments include removal of autoantibodies with plasma exchange or broad immunosuppression and chemotherapy, often with treatment-limiting side effects including sepsis or even death. Currently, there is no treatment that selectively depletes the pathogenic NR1 autoantibodies while leaving the majority of beneficial antibodies unchanged. Thus, there is an urgent need for highly selective therapies that specifically deplete the disease-relevant NR1 autoantibodies.
The technology exploits the unique B-cell receptor to selectively destroy the NR1 antibody-producing pathogenic B-cells. The target is the antigen-binding part of the NR1 autoantibody, localized exclusively in the membrane of disease-relevant B cells. The strategy utilizes chimeric autoantibody receptor (CAAR) T-cells in which the extracellular domain of the CAAR consists of fragments of the NMDAR. This allows CAAR T-cells to specifically bind and destroy NR1 antibody-producing B-cells, the drivers of NMDAR encephalitis and directly responsible for the disease, but not affecting other B-cells. Successful validation will likely result in the first-in-class disease-specific immunotherapy in patients with NR1 antibody-mediated neuropsychiatric disorders. Expected outcomes are markedly reduced side effects, immediate treatment effects, much faster recovery with reduced morbidity and long-term brain damage and reduced costs. The proposed CAAR T-cell therapy aims for a curative approach with long-term recovery.
Licensing and/or co-development.
Ellebrecht et.al., Science 2016. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease.