Kanno Atsuo, Kito Takuya, Maeda Masashi, Yamaki Shanni, Amano Yasushi, Shimomura Takuya, Anisimova Margarita, Kanazawa Naomi, Suzuki Koichiro, Razai Amir, Mihara Takuma, Kubo Kaori, Shimada Takeshi, Nakamura Koji, Nomura Naoko, Kondo Yuji, Okimoto Akira, Sugiyama Azusa, Park Deborah, Stein Ivar, Petshow Samuel, Vandendoren Valentin, Bilic Sanela, Kazimi Roghiye, Eastman Vallari, Snipas Scott J, Mitchell Mathew, Maurer Mari, Jefson Marty, Lichter Jay, Yamajuku Daisuke, Shirai Hiroki, Adachi Megumi, Hoeppner Daniel J, Kubo Satoshi, Zito Karen, Iizuka Takahiro, Flynn Peter, Matsumoto Mitsuyuki
Arialys Therapeutics, Inc., La Jolla, CA, USA.
Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
Nat Commun. 2025 Jun 17;16(1):5292. doi: 10.1038/s41467-025-60628-1.
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 = 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.
抗N-甲基-D-天冬氨酸受体（NMDAR）脑炎是一种具有严重精神和神经症状的毁灭性疾病，据信是由与NMDAR GluN1亚基（GluN1-NTD）的N端结构域（NTD）结合的致病性自身抗体引起的，这些抗体使相邻的NMDAR交联并促使其内化。在此，我们描述了一种人源化单价抗体ART5803，它有望成为治疗抗NMDAR脑炎的药物。ART5803以高亲和力（K = 0.69 nM）与GluN1-NTD结合，而不影响NMDAR活性或诱导其内化。ART5803可阻断患者致病性自身抗体诱导的NMDAR内化，并恢复NMDAR功能。通过持续脑室内（ICV）注射人致病性自身抗体建立了狨猴动物模型，以诱发行为和运动异常。ART5803经ICV输注或外周注射可迅速逆转这些异常。这些数据，连同食蟹猴的药代动力学特征，表明静脉注射（IV）ART5803作为抗NMDAR脑炎的一种速效且有效的治疗选择具有治疗潜力。
