TY  - JOUR
AU  - Reincke, Momsen
AU  - von-Wardenburg, Niels-Oliver
AU  - Homeyer, Marie Alice
AU  - Kornau, Hans-Christian
AU  - Spagni, Gregorio
AU  - Li, Lucie Y
AU  - Kreye, Jakob
AU  - Sánchez-Sendín, Elisa
AU  - Blumenau, Sonja
AU  - Stappert, Dominik
AU  - Radbruch, Helena
AU  - Hauser, Anja E
AU  - Künkele, Annette
AU  - Edes, Inan
AU  - Schmitz, Dietmar
AU  - Prüss, Harald
TI  - Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells.
JO  - Cell
VL  - 186
IS  - 23
SN  - 0092-8674
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2023-01062
SP  - 5084 - 5097.e18
PY  - 2023
AB  - Anti-NMDA receptor (NMDAR) autoantibodies cause NMDAR encephalitis, the most common autoimmune encephalitis, leading to psychosis, seizures, and autonomic dysfunction. Current treatments comprise broad immunosuppression or non-selective antibody removal. We developed NMDAR-specific chimeric autoantibody receptor (NMDAR-CAAR) T cells to selectively eliminate anti-NMDAR B cells and disease-causing autoantibodies. NMDAR-CAARs consist of an extracellular multi-subunit NMDAR autoantigen fused to intracellular 4-1BB/CD3ζ domains. NMDAR-CAAR T cells recognize a large panel of human patient-derived autoantibodies, release effector molecules, proliferate, and selectively kill antigen-specific target cell lines even in the presence of high autoantibody concentrations. In a passive transfer mouse model, NMDAR-CAAR T cells led to depletion of an anti-NMDAR B cell line and sustained reduction of autoantibody levels without notable off-target toxicity. Treatment of patients may reduce side effects, prevent relapses, and improve long-term prognosis. Our preclinical work paves the way for CAAR T cell phase I/II trials in NMDAR encephalitis and further autoantibody-mediated diseases.
KW  - Animals
KW  - Humans
KW  - Mice
KW  - Autoantibodies: metabolism
KW  - Encephalitis: metabolism
KW  - Encephalitis: therapy
KW  - Receptors, N-Methyl-D-Aspartate
KW  - T-Lymphocytes
KW  - Autoimmune Diseases
KW  - Disease Models, Animal
KW  - CAAR T cell (Other)
KW  - CAAR T cell (Other)
KW  - CAAR T cell (Other)
KW  - CAAR T cell (Other)
KW  - CAAR T cell (Other)
KW  - CAAR T cell (Other)
KW  - NMDA receptor encephalitis (Other)
KW  - T cells (Other)
KW  - autoimmune encephalitis (Other)
KW  - autoimmunity (Other)
KW  - cell therapy (Other)
KW  - chimeric autoantibody receptor (Other)
KW  - Autoantibodies (NLM Chemicals)
KW  - Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37918394
DO  - DOI:10.1016/j.cell.2023.10.001
UR  - https://pub.dzne.de/record/265939
ER  -