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 and Mitsuyuki Matsumoto ()
Additional contact information
Atsuo Kanno: Inc.
Takuya Kito: Tsukuba
Masashi Maeda: Inc.
Shanni Yamaki: Inc.
Yasushi Amano: Tsukuba
Takuya Shimomura: Tsukuba
Margarita Anisimova: University of California
Naomi Kanazawa: Kitasato University School of Medicine
Koichiro Suzuki: Tsukuba
Amir Razai: Inc.
Takuma Mihara: Tsukuba
Kaori Kubo: Tsukuba
Takeshi Shimada: Tsukuba
Koji Nakamura: Tsukuba
Naoko Nomura: Tsukuba
Yuji Kondo: Tsukuba
Akira Okimoto: Tsukuba
Azusa Sugiyama: Tsukuba
Deborah Park: University of California
Ivar Stein: University of California
Samuel Petshow: University of California
Valentin Vandendoren: LLC
Sanela Bilic: LLC
Roghiye Kazimi: Inc.
Vallari Eastman: Inc.
Scott J. Snipas: Inc.
Mathew Mitchell: Inc.
Mari Maurer: Inc.
Marty Jefson: Inc.
Jay Lichter: Inc.
Daisuke Yamajuku: Tsukuba
Hiroki Shirai: Tsukuba
Megumi Adachi: Tsukuba
Daniel J. Hoeppner: Tsukuba
Satoshi Kubo: Inc.
Karen Zito: University of California
Takahiro Iizuka: Kitasato University School of Medicine
Peter Flynn: Inc.
Mitsuyuki Matsumoto: Inc.

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60628-1

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DOI: 10.1038/s41467-025-60628-1

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