What Is the Potential of a Monovalent Antibody in Anti-NMDA Receptor Encephalitis?

Immunosuppression and Immunomodulation Are Not Always Enough

Anti-NMDA receptor encephalitis (anti-NMDAR encephalitis) is a rare autoimmune disease that primarily affects young patients. It manifests through a spectrum of psychiatric, neurological, and cognitive symptoms, including behavioral changes, hallucinations, epileptic seizures, dyskinesias, and altered consciousness.

The disease is mediated by IgG-class autoantibodies that bind to NMDA receptors, causing receptor cross-linking and subsequent internalization. This leads to a functional receptor deficit and disrupted glutamatergic neurotransmission.

Current therapy is nonspecific and includes immunosuppressive treatment, plasma exchange, immunoglobulin administration, or surgical removal of an associated tumor. However, mortality and morbidity remain high, recovery is prolonged, relapses are common, and many patients experience lasting cognitive deficits. These factors highlight the unmet medical need for specifically targeted therapeutic approaches.

A New Concept: Monovalent Antibody

The study authors developed a humanized monoclonal antibody that binds to the same NMDA receptor epitope as the patient’s pathogenic autoantibodies.

A key feature of the construct is its monovalent nature. The antibody has only one binding site and therefore does not induce receptor cross-linking or internalization. It can selectively block the binding of pathogenic IgG antibodies without interfering with normal NMDA receptor function. Unlike current nonspecific immunosuppressive therapy, this approach targets the core mechanism of anti-NMDAR encephalitis directly.

Preclinical Validation

In Vitro and Ex Vivo Models

In cell cultures, the authors successfully demonstrated that the experimental antibody competitively blocks patient-derived IgG from binding to NMDA receptors, preventing their internalization. Measurement of NMDA-induced Ca²⁺ influx showed that the antibody itself does not affect receptor function.

In cultured mouse hippocampal slices, restoration of NMDA receptor expression on cell surfaces and recovery of dendritic spine morphology were observed.

The antibody was also tested on serum samples from patients with anti-NMDAR encephalitis. In the presence of the developed antibody, receptor internalization did not occur, confirming its efficacy against actual human autoantibodies—not just experimental ones.

In Vivo Efficacy

In tree shrews, evolutionarily close to primates, continuous intracerebroventricular (ICV) infusion of human pathogenic autoantibodies induced behavioral and motor disturbances resembling those seen in anti-NMDAR encephalitis.

Co-infusion of the pathogenic antibody with the experimental antibody reversed these changes. Even peripheral intraperitoneal administration reduced abnormal behavior after one week. These data demonstrate a potential peripheral route of administration in patients: despite the limited penetration of monoclonal antibodies into the CNS, a 400 mg/kg dose achieved the required target concentration in cerebrospinal fluid.

A safety study in macaques established pharmacokinetic profiles and CNS penetration, which were then used to model human dosing. Simulation predicted that achieving a target CSF concentration of 0.6–2.5 µg/ml in patients would require weekly intravenous administration of 40–100 mg/kg.

These findings suggest that intravenously administered experimental antibody therapy could offer a fast-acting and effective treatment option for anti-NMDAR encephalitis. The antibody was well tolerated in primate models, with no signs of neurotoxicity or serious adverse effects.

Summary of Preclinical Findings and Next Steps

This study provides the first evidence that a humanized monovalent monoclonal antibody can selectively block the pathogenic mechanism of anti-NMDAR encephalitis while preserving normal receptor function. Its efficacy was confirmed across a range of preclinical models—from cell cultures and brain slices to primates, including tests using patient serum samples. Safety evaluation revealed no neurotoxicity.

The authors emphasize that their work “provides preclinical proof of concept for a new targeted therapy in anti-NMDAR encephalitis” and opens the path toward clinical trials. According to them, the results indicate the possibility of developing a therapeutic approach that, for the first time, targets the fundamental pathogenic mechanism of this severe disease.

Editorial Team, Medscope.pro

Source:

Kanno A., Kito T., Maeda M. et al. Monoclonal humanized monovalent antibody blocking therapy for anti-NMDA receptor encephalitis. Nat Commun 16, 5292 (2025), doi: 10.1038/s41467-025-60628-1.