Rudy Michael J, Wilson Courtney J, Hinckley Brendan, Baker Danielle C, Royal Joshua M, Hoke Marshall P, Brennan Miles B, Vogt Matthew R, Clarke Penny, Tyler Kenneth L
Department of Neurology, University of Colorado, Aurora, Colorado, USA.
Department of Research and Discovery, KBio Inc., Owensboro, Kentucky, USA.
mBio. 2025 Apr 9;16(4):e0390624. doi: 10.1128/mbio.03906-24. Epub 2025 Mar 24.
In 2014, 2016, and 2018, infection with enterovirus D68 (EV-D68) was associated with outbreaks of a poliomyelitis-like paralytic syndrome, called acute flaccid myelitis (AFM). While only a small fraction of patients infected with EV-D68 developed AFM, this subgroup of patients does not typically seek treatment until after the onset of neurological symptoms. There are currently no approved human monoclonal antibody therapies or vaccines available for EV-D68. Here, we show that a monoclonal antibody, EV68-228-N, can quickly stop the progression of paralysis in a mouse model of AFM, even when treatment is initiated after the onset of paralysis. We found that EV68-228-N effectively halted the progression of paralysis when tested against both 2014 and 2016 EV-D68 isolates in an immunocompetent mouse model of AFM. All animal experiments were conducted in a blinded fashion. The IC of EV68-228-N against 2014 and 2016 EV-D68 isolates was confirmed to be less than 330 ng/mL, and EV68-228-N was found to be equally effective at neutralizing 2018 and 2022 viral isolates without any evidence of emerging resistance. We further show that, following infection with EV-D68, mice treated with EV68-228-N have more surviving motor neurons in the spinal cord's lumbar enlargement than control treated animals. Taken together, this work suggests that EV68-228-N treatment has the potential to halt the progression of paralysis in AFM patients who present at the clinic with neurologic symptoms and that EV68-228-N will retain neutralization potential against emerging EV-D68 isolates.
Enterovirus D-68 (EV-D68) associated acute flaccid myelitis (AFM) is an emergent poliomyelitis-like illness occurring predominantly in children. There are currently no proven effective therapies. We describe the use of a human monoclonal antibody (EV68-228-N) in a murine model of EV-D68 AFM in which therapy prevents progression of paralysis even when treatment is instituted after onset of weakness.
This study is registered with ClinicalTrials.gov as NCT06444048.
2014年、2016年和2018年，肠道病毒D68（EV-D68）感染与一种类似脊髓灰质炎的麻痹综合征（称为急性弛缓性脊髓炎，AFM）的暴发有关。虽然感染EV-D68的患者中只有一小部分会发展为AFM，但这一亚组患者通常直到出现神经症状后才寻求治疗。目前尚无批准用于EV-D68的人源单克隆抗体疗法或疫苗。在此，我们表明，一种单克隆抗体EV68-228-N能够在AFM小鼠模型中迅速阻止麻痹的进展，即使在麻痹发作后开始治疗也是如此。我们发现，在具有免疫活性的AFM小鼠模型中，用EV68-228-N针对2014年和2016年的EV-D68分离株进行测试时，它能有效阻止麻痹的进展。所有动物实验均以盲法进行。EV68-228-N针对2014年和2016年EV-D68分离株的半数抑制浓度（IC）经确认小于330 ng/mL，并且发现EV68-228-N在中和2018年和2022年的病毒分离株时同样有效，没有出现任何耐药迹象。我们进一步表明，在感染EV-D68后，用EV68-228-N治疗的小鼠脊髓腰膨大处存活的运动神经元比对照治疗的动物更多。综上所述，这项研究表明，EV68-228-N治疗有可能阻止临床上出现神经症状的AFM患者的麻痹进展，并且EV68-228-N对新出现的EV-D68分离株将保留中和潜力。
肠道病毒D-68（EV-D68）相关的急性弛缓性脊髓炎（AFM）是一种主要发生在儿童中的类似脊髓灰质炎的新发疾病。目前尚无经证实有效的疗法。我们描述了在EV-D68 AFM小鼠模型中使用人源单克隆抗体（EV68-228-N），在该模型中，即使在出现肌无力后开始治疗，该疗法也能阻止麻痹的进展。
本研究已在ClinicalTrials.gov注册，注册号为NCT06444048。
