First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury
First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury
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DOI：
10.1177/1545968318776371
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发表时间：
2018-06-01
影响因子：
4.2
通讯作者：
Curt, Armin
中科院分区：
文献类型：
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作者：
Kucher, Klaus;Johns, Donald;Curt, Armin
背景中枢神经系统神经突生长抑制因子（例如Nogo-A）的中和是改善脊髓损伤（SCI）后恢复的有希望的方法。在SCI动物模型中，鞘内注射抗Nogo-A抗体可促进再生神经突起生长和功能恢复。Objective.这项首次人体研究评估了人抗Nogo-A抗体ATI 355在急性完全创伤性截瘫和四肢瘫痪患者中鞘内给药后的可行性、安全性、耐受性、药代动力学和初步疗效。方法.患者（N = 52）在伤后4至60天开始治疗。四个连续剂量递增队列在24小时至28天内接受5至30 mg/2.5 mL/天连续鞘内ATI 355输注。在药代动力学评价后，另外2个队列接受推注方案（6次鞘内注射，分别为22.5和45 mg/3 mL，持续4周）。结果ATI 355在长达1年的随访中耐受性良好。所有患者均发生1起不良事件（AE）。报告的581起AE大多为轻度，预期发生于急性SCI后。15例患者报告了16起严重AE，均与ATI 355无关; 1例细菌性脑膜炎病例被认为与鞘内给药有关。ATI 355血清水平呈剂量依赖性，输注和推注后受试者间脑脊液水平高度可变。在1例截瘫患者中，运动评分改善了8分。在四肢瘫痪患者中，平均总运动评分增加，其中3/19在第48周获得>10分，1/19获得27分。19例四肢瘫患者中有7例从完全性脊髓损伤转为不完全性脊髓损伤。结论. ATI 335在人体中耐受性良好;在急性SCI中可以考虑使用鞘内抗体给药的疗效试验。
Background. Neutralization of central nervous system neurite growth inhibitory factors, for example, Nogo-A, is a promising approach to improving recovery following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of anti-Nogo-A antibodies promoted regenerative neurite growth and functional recovery. Objective. This first-in-man study assessed the feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administration in patients with acute, complete traumatic paraplegia and tetraplegia. Methods. Patients (N = 52) started treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, respectively, over 4 weeks). Results. ATI355 was well tolerated up to 1-year follow-up. All patients experienced 1 adverse events (AEs). The 581 reported AEs were mostly mild and to be expected following acute SCI. Fifteen patients reported 16 serious AEs, none related to ATI355; one bacterial meningitis case was considered related to intrathecal administration. ATI355 serum levels showed dose-dependency, and intersubject cerebrospinal fluid levels were highly variable after infusion and bolus injection. In 1 paraplegic patient, motor scores improved by 8 points. In tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from complete to incomplete SCI occurred in 7/19 patients with tetraplegia. Conclusions. ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI.