Monoclonal humanized monovalent antibody blocking therapy for anti-NMDA receptor encephalitis
- Atsuo Kanno
- Takuya Kito
- Masashi Maeda
- Shanni Yamaki
- Yasushi Amano
- Takuya Shimomura
- Margarita Anisimova
- Naomi Kanazawa
- Koichiro Suzuki
- Amir Razai
- Takuma Mihara
- Kaori Kubo
- Takeshi Shimada
- Koji Nakamura
- Naoko Nomura
- Yuji Kondo
- Akira Okimoto
- Azusa Sugiyama
- Deborah Park
- Ivar Stein
- Samuel Petshow
- Valentin Vandendoren
- Sanela Bilic
- Roghiye Kazimi
- Vallari Eastman
- Scott J. Snipas
- Mathew Mitchell
- Mari Maurer
- Marty Jefson
- Jay Lichter
- Daisuke Yamajuku
- Hiroki Shirai
- Megumi Adachi
- Daniel J. Hoeppner
- Satoshi Kubo
- Karen Zito
- Takahiro Iizuka
- Peter Flynn
- Mitsuyuki Matsumoto
2025-06-17
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 D = 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.