Monoclonal humanized monovalent antibody blocking therapy for anti-NMDA receptor encephalitis
Anti-NMDA receptor (NMDAR) encephalitis is a devastating disease with severe psychiatric and neurological symptoms believed to be caused by pathogenic autoantibodies that bind to the N-terminal domain (NTD) of the NMDAR GluN1 subunit (GluN1-NTD) crosslinking adjacent NMDARs and driving their internalization. Here we describe ART5803, a humanized monovalent antibody, as a potential therapy for anti-NMDAR encephalitis. ART5803 binds with a high affinity (K<sub>D</sub> = 0.69 nM) to GluN1-NTD without affecting NMDAR activity or inducing internalization. ART5803 blocks NMDAR internalization induced by patients' pathogenic autoantibodies, and restores NMDAR function. A marmoset animal model was developed using sustained intracerebroventricular (ICV) administration of a human pathogenic autoantibody to evoke behavioral and motor abnormalities. ART5803 ICV infusion or peripheral injections rapidly reversed these abnormalities. These data, together with the pharmacokinetic profile in cynomolgus monkeys, indicate a therapeutic potential for intravenous (IV)-administered ART5803 as a fast-acting and efficacious option for anti-NMDAR encephalitis.
Authors
- Akira Okimoto (ORCID: https://orcid.org/0000-0003-3115-2800)
- Yuji Kondo (ORCID: https://orcid.org/0000-0001-7599-1716)
- Mathew Mitchell
- Koichiro Suzuki
- Roghiye Kazimi
- Amir S. Razai (ORCID: https://orcid.org/0000-0002-7172-0713)
- Margarita Anisimova (ORCID: https://orcid.org/0000-0003-1557-7358)
- Deborah Park
- Daniel J. Hoeppner (ORCID: https://orcid.org/0000-0002-0886-5215)
- Megumi Adachi (ORCID: https://orcid.org/0000-0003-3404-6640)
- Takuya Shimomura (ORCID: https://orcid.org/0000-0002-6769-4655)
- Azusa Sugiyama
- Martin R. Jefson
- Daisuke Yamajuku
- Karen Zito (ORCID: https://orcid.org/0000-0002-0799-0460)
- Y. Amano (ORCID: https://orcid.org/0000-0002-7190-7537)
- Shanni Yamaki
- Takahiro Iizuka (ORCID: https://orcid.org/0000-0002-7234-0720)
- Samuel Petshow (ORCID: https://orcid.org/0000-0002-7989-3598)
- Satoshi Kubo (ORCID: https://orcid.org/0000-0001-9693-9263)
- Mitsuyuki Matsumoto (ORCID: https://orcid.org/0000-0002-1172-2354)
- Peter Flynn (ORCID: https://orcid.org/0009-0008-7704-3718)
- Vallari R. Eastman
- Naomi Kanazawa (ORCID: https://orcid.org/0000-0001-8027-4447)
- Koji Nakamura (ORCID: https://orcid.org/0000-0002-5473-2069)
- Ivar S. Stein (ORCID: https://orcid.org/0009-0006-8894-2781)
- Scott J. Snipas (ORCID: https://orcid.org/0000-0002-4239-6862)
- Takuya Kito (ORCID: https://orcid.org/0009-0009-9355-3870)
- Sanela Bilic (ORCID: https://orcid.org/0009-0007-0181-7134)
- Takeshi Shimada (ORCID: https://orcid.org/0000-0001-5763-8994)
- Jay B. Lichter
- Atsuo Kanno
- Mari Maurer
- Naoko Nomura
- Hiroki Shirai
- Takuma Mihara
- Masashi Maeda
- Kaori Kubo
- Valentin Vandendoren
Institutions
- Astellas Pharma (Japan) (JP)
- AXYS Technologies (Canada) (CA)
- Io Therapeutics (United States) (US)
- Kitasato University (JP)
- University of California, Davis (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1038/s41467-025-60628-1
- Citations
- 7
- Primary Topic
- Autoimmune Neurological Disorders and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 9.72
Funders
- Astellas Pharma