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

  • Nat Commun. 2025 Jun 17;16(1):5292. doi: 10.1038/s41467-025-60628-1.
Atsuo Kanno  #  1  2 Takuya Kito  #  2 Masashi Maeda  1  2 Shanni Yamaki  1 Yasushi Amano  2 Takuya Shimomura  2 Margarita Anisimova  3 Naomi Kanazawa  4 Koichiro Suzuki  2 Amir Razai  1 Takuma Mihara  2 Kaori Kubo  2 Takeshi Shimada  2 Koji Nakamura  2 Naoko Nomura  2 Yuji Kondo  2 Akira Okimoto  2 Azusa Sugiyama  2 Deborah Park  3 Ivar Stein  3 Samuel Petshow  3 Valentin Vandendoren  5 Sanela Bilic  5 Roghiye Kazimi  1 Vallari Eastman  1 Scott J Snipas  1 Mathew Mitchell  1 Mari Maurer  1 Marty Jefson  1 Jay Lichter  1 Daisuke Yamajuku  2 Hiroki Shirai  2 Megumi Adachi  2 Daniel J Hoeppner  2 Satoshi Kubo  1  2 Karen Zito  3 Takahiro Iizuka  4 Peter Flynn  1 Mitsuyuki Matsumoto  6  7
Affiliations
  • 1. Arialys Therapeutics, Inc., La Jolla, CA, USA.
  • 2. Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
  • 3. Center for Neuroscience, University of California, Davis, CA, USA.
  • 4. Department of Neurology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
  • 5. Vanadro, LLC, Waukee, IA, USA.
  • 6. Arialys Therapeutics, Inc., La Jolla, CA, USA. [email protected].
  • 7. Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. [email protected].
  • # Contributed equally.
Abstract

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 (KD = 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.

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