2. Academic Validation
  3. Monoclonal humanized monovalent antibody blocking therapy for anti-NMDA receptor encephalitis

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

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. mmatsumoto@arialysrx.com.
  • 7 Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. mmatsumoto@arialysrx.com.
  • # Contributed equally.
PMID: 40527893 DOI: 10.1038/s41467-025-60628-1
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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