NMDA-receptor-Fc-fusion constructs neutralize anti-NMDA receptor antibodies

Area of Science:

• Neuroimmunology
• Molecular Neuroscience
• Therapeutic Development

Background:

• N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disorder causing neuropsychiatric symptoms, often linked to antibodies targeting the GluN1 subunit.
• Current immunotherapy for NMDAR encephalitis can have delayed effects, necessitating faster treatment strategies.
• Understanding the precise epitopes targeted by NMDAR antibodies is crucial for developing effective therapies.

Purpose of the Study:

• To develop novel fusion constructs for rapid neutralization of NMDAR antibodies.
• To investigate the role of GluN1 and GluN2 subunits in forming high-affinity epitopes for NMDAR antibodies.
• To evaluate the therapeutic potential of these constructs in preclinical models of NMDAR encephalitis.

Main Methods:

• Engineered fusion constructs combining the Fc region of IgG with NMDAR amino-terminal domains (GluN1, or GluN1 with GluN2A/GluN2B).
• Assessed construct binding to patient-derived antibodies and cerebrospinal fluid (CSF).
• Investigated effects on NMDAR internalization in neuronal cultures and NMDAR currents in rodent neurons.
• Evaluated memory rescue in passive-transfer mouse models.

Main Results:

• Fusion constructs incorporating both GluN1 and GluN2 subunits effectively generated high-affinity epitopes.
• The GluN1/GluN2B construct neutralized patient-derived NMDAR antibodies and inhibited NMDAR internalization.
• The construct stabilized NMDAR currents and rescued memory deficits in mouse models.
• Identified GluN1 and GluN2B subunits as key contributors to the main immunogenic region of NMDAR.

Conclusions:

• A novel fusion construct targeting GluN1 and GluN2B subunits shows potential for rapid treatment of NMDAR encephalitis.
• This approach could complement existing immunotherapies by offering faster antibody neutralization.
• The findings highlight the importance of specific NMDAR subunit interactions in autoimmune responses and therapeutic design.