Monoclonal humanized monovalent antibody blocking therapy for anti-NMDA receptor encephalitis

PMCID: PMC12174348

PMID: 40527893

DOI: 10.1038/s41467-025-60628-1

Journal: Nature communications

Publication Date: 2025-6-17

Authors: Kanno A, Kito T, Maeda M, Yamaki S, Amano Y, et al.

Key Points

• First monovalent antibody designed to specifically block pathogenic NMDAR autoantibodies without receptor dysfunction
• Demonstrated 74% reversal of NMDAR internalization at 2.5 μg/mL concentration in preclinical models
• Offers a targeted therapeutic approach with potential to rapidly mitigate neurological and psychiatric symptoms of anti-NMDAR encephalitis

Summary

This groundbreaking study introduces ART5803, a novel humanized monovalent antibody targeting N-methyl-D-aspartate receptor (NMDAR) encephalitis, a devastating autoimmune neurological disorder. By developing a sophisticated therapeutic approach, researchers created an antibody that can block pathogenic autoantibodies from causing NMDAR internalization without disrupting receptor function. Using advanced molecular engineering techniques, including knobs-into-hole and LALA mutations, ART5803 was designed to bind with high affinity (KD = 0.69 nM) to the GluN1 subunit's N-terminal domain while avoiding immune-mediated cytotoxicity.

The research validated ART5803's therapeutic potential through a marmoset animal model, demonstrating its ability to rapidly reverse behavioral and motor abnormalities induced by pathogenic autoantibodies. By precisely targeting the specific epitope responsible for NMDAR crosslinking and internalization, ART5803 represents a promising intervention that could fundamentally transform treatment strategies for anti-NMDAR encephalitis. The study's findings suggest a potential fast-acting and efficacious therapeutic option that could significantly improve patient outcomes in this challenging neurological condition.