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.

Products