Monoclonal humanized monovalent antibody blocking therapy for anti-NMDA receptor encephalitis
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.
Article Details
Authors (39)
Atsuo Kanno
Takuya Kito
Masashi Maeda
Shanni Yamaki
Yasushi Amano
Takuya Shimomura
Margarita Anisimova
Naomi Kanazawa
Koichiro Suzuki
Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University
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
Center for Neuroscience, University of California
Takahiro Iizuka
Peter Flynn
Mitsuyuki Matsumoto