Journal Article

DZNE-2023-00512

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NMDA-receptor-Fc-fusion constructs neutralize anti-NMDA receptor antibodies.

Steinke, S. ; Kirmann, T. ; Loi, E. A. ; Nerlich, J. ; Weichard, I. ; Kuhn, P. ; Bullmann, T. ; Ritzau-Jost, A. ; Rizalar, F. S. ; Prüss, H.DZNE* ; Haucke, V. ; Geis, C. ; Hust, M. ; Hallermann, S.

2023
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awac497

Abstract: N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common subtype of autoimmune encephalitis characterized by a complex neuropsychiatric syndrome usually including memory impairment. Patients develop an intrathecal immune response against NMDARs with antibodies that presumably bind to the amino-terminal domain of the GluN1 subunit. The therapeutic response to immunotherapy is often delayed. Therefore, new therapeutic approaches for fast neutralization of NMDAR antibodies are needed. Here, we developed fusion constructs consisting of the Fc part of immunoglobulin G and the amino-terminal domains of either GluN1 or combinations of GluN1 with GluN2A or GluN2B. Surprisingly, both GluN1 and GluN2 subunits were required to generate high-affinity epitopes. The construct with both subunits efficiently prevented NMDAR binding of patient-derived monoclonal antibodies and of patient CSF containing high-titre NMDAR antibodies. Furthermore, it inhibited the internalization of NMDARs in rodent dissociated neurons and human induced pluripotent stem cell-derived neurons. Finally, the construct stabilized NMDAR currents recorded in rodent neurons and rescued memory defects in passive-transfer mouse models using intrahippocampal injections. Our results demonstrate that both GluN1 and GluN2B subunits contribute to the main immunogenic region of the NMDAR and provide a promising strategy for fast and specific treatment of NMDAR encephalitis, which could complement immunotherapy.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Encephalitis (MeSH) ; Autoantibodies: metabolism (MeSH) ; Hashimoto Disease (MeSH) ; NMDA receptor ; antibodies bodies ; autoimmune encephalitis ; memory ; synapses ; Receptors, N-Methyl-D-Aspartate ; Autoantibodies

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Contributing Institute(s):

1. Autoimmune Enzephalopathies (AG Prüß)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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