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. 2023 Nov 9;186(23):5084-5097.e18.
doi: 10.1016/j.cell.2023.10.001. Epub 2023 Nov 1.

Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells

S Momsen Reincke  1 , Niels von Wardenburg  2 , Marie A Homeyer  3 , Hans-Christian Kornau  4 , Gregorio Spagni  5 , Lucie Y Li  3 , Jakob Kreye  6 , Elisa Sánchez-Sendín  3 , Sonja Blumenau  7 , Dominik Stappert  8 , Helena Radbruch  9 , Anja E Hauser  10 , Annette Künkele  11 , Inan Edes  12 , Dietmar Schmitz  4 , Harald Prüss  13
Affiliations
Free article

Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells

S Momsen Reincke et al. Cell. .
Free article

Abstract

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.

Keywords: CAAR T cell; NMDA receptor encephalitis; T cells; autoimmune encephalitis; autoimmunity; cell therapy; chimeric autoantibody receptor.

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Conflict of interest statement

Declaration of interests Related to this work, the German Center for Neurodegenerative Diseases (DZNE) and Max-Delbrück-Centrum Berlin have filed a patent application describing NMDAR-CAAR T cells for treatment of NMDAR encephalitis on which S.M.R., I.E., and H.P. are named as inventors (WO/2020/245343). In addition, the DZNE has filed a patent application on constructs for detection and isolation of NMDAR autoantibodies on which H.-C.K. and H.P. are named as inventors (WO/2021/008890).

Comment in

  • CAAR T cells to treat encephalitis.
    Crunkhorn S. Crunkhorn S. Nat Rev Drug Discov. 2024 Jan;23(1):22. doi: 10.1038/d41573-023-00193-8. Nat Rev Drug Discov. 2024. PMID: 38040791 No abstract available.

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