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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月17日

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  • 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

摘要

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.