PMID- 36866449
OWN - NLM
STAT- MEDLINE
DCOM- 20230503
LR  - 20230504
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Print)
IS  - 0006-8950 (Linking)
VI  - 146
IP  - 5
DP  - 2023 May 2
TI  - NMDA-receptor-Fc-fusion constructs neutralize anti-NMDA receptor antibodies.
PG  - 1812-1820
LID - 10.1093/brain/awac497 [doi]
AB  - 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.
CI  - (c) The Author(s) 2023. Published by Oxford University Press on behalf of the 
      Guarantors of Brain.
FAU - Steinke, Stephan
AU  - Steinke S
AUID- ORCID: 0000-0001-8559-954X
AD  - Technische Universitat Braunschweig, Institut fur Biochemie, Biotechnologie und 
      Bioinformatik, Department Medizinische Biotechnologie, Braunschweig 38106, 
      Germany.
FAU - Kirmann, Toni
AU  - Kirmann T
AUID- ORCID: 0000-0003-1985-5095
AD  - Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University, 
      Leipzig 04103, Germany.
FAU - Loi, Eleonora A
AU  - Loi EA
AD  - Section Translational Neuroimmunology, Department for Neurology, Jena University 
      Hospital, 07747 Jena, Germany.
FAU - Nerlich, Jana
AU  - Nerlich J
AD  - Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University, 
      Leipzig 04103, Germany.
FAU - Weichard, Iron
AU  - Weichard I
AD  - Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University, 
      Leipzig 04103, Germany.
FAU - Kuhn, Philipp
AU  - Kuhn P
AD  - YUMAB GmbH, Braunschweig 38124, Germany.
FAU - Bullmann, Torsten
AU  - Bullmann T
AD  - Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University, 
      Leipzig 04103, Germany.
FAU - Ritzau-Jost, Andreas
AU  - Ritzau-Jost A
AD  - Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University, 
      Leipzig 04103, Germany.
FAU - Rizalar, Filiz Sila
AU  - Rizalar FS
AD  - Department of Molecular Pharamcology and Cell Biology, Leibniz-Forschungsinstitut 
      fur Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
AD  - Faculty of Biology, Chemistry, Pharmacy, Freie Universitat Berlin, Berlin 14195, 
      Germany.
FAU - Pruss, Harald
AU  - Pruss H
AD  - German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin 10117, 
      Germany.
AD  - Department of Neurology and Experimental Neurology, Charite-Universitatsmedizin 
      Berlin, 10117 Berlin, Germany.
FAU - Haucke, Volker
AU  - Haucke V
AD  - Department of Molecular Pharamcology and Cell Biology, Leibniz-Forschungsinstitut 
      fur Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
AD  - Faculty of Biology, Chemistry, Pharmacy, Freie Universitat Berlin, Berlin 14195, 
      Germany.
FAU - Geis, Christian
AU  - Geis C
AUID- ORCID: 0000-0002-9859-581X
AD  - Section Translational Neuroimmunology, Department for Neurology, Jena University 
      Hospital, 07747 Jena, Germany.
FAU - Hust, Michael
AU  - Hust M
AUID- ORCID: 0000-0003-3418-6045
AD  - Technische Universitat Braunschweig, Institut fur Biochemie, Biotechnologie und 
      Bioinformatik, Department Medizinische Biotechnologie, Braunschweig 38106, 
      Germany.
FAU - Hallermann, Stefan
AU  - Hallermann S
AUID- ORCID: 0000-0001-9376-7048
AD  - Faculty of Medicine, Carl-Ludwig-Institute of Physiology, Leipzig University, 
      Leipzig 04103, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Autoantibodies)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Humans
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - *Induced Pluripotent Stem Cells/metabolism
MH  - *Encephalitis
MH  - Autoantibodies/metabolism
MH  - *Hashimoto Disease
PMC - PMC10151181
OTO - NOTNLM
OT  - NMDA receptor
OT  - antibodies bodies
OT  - autoimmune encephalitis
OT  - memory
OT  - synapses
COIS- H.P. has a patent application pending for the use of similar NMDAR-Fc chimeras in 
      autoimmune diseases.
EDAT- 2023/03/04 06:00
MHDA- 2023/05/03 06:42
PMCR- 2023/03/03
CRDT- 2023/03/03 03:12
PHST- 2022/04/29 00:00 [received]
PHST- 2022/11/15 00:00 [revised]
PHST- 2022/12/12 00:00 [accepted]
PHST- 2023/05/03 06:42 [medline]
PHST- 2023/03/04 06:00 [pubmed]
PHST- 2023/03/03 03:12 [entrez]
PHST- 2023/03/03 00:00 [pmc-release]
AID - 7067285 [pii]
AID - awac497 [pii]
AID - 10.1093/brain/awac497 [doi]
PST - ppublish
SO  - Brain. 2023 May 2;146(5):1812-1820. doi: 10.1093/brain/awac497.