针对肌萎缩侧索硬化症的 CD14 单克隆抗体 IC14 的 1b 期剂量递增、安全性和药代动力学研究。
Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis.
机构信息
Royal Brisbane & Women's Hospital, Herston, Queensland, Australia.
University of Queensland, Centre for Clinical Research, Herston, Queensland, Australia.
出版信息
Medicine (Baltimore). 2021 Oct 22;100(42):e27421. doi: 10.1097/MD.0000000000027421.
BACKGROUND
The primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers.
METHODS
In this open-label, dose-escalation trial, IC14 was administered at 2 mg/kg intravenous (IV) followed by 1 mg/kg/d IV × 3 (n = 3) and in subsequent patients at 4 mg/kg IV followed by 2 mg/kg/d IV × 3 (n = 7) (NCT03487263). Disease status was measured using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, Edinburgh Cognitive and Behavioural ALS Screen, and Revised ALS-Specific Quality-of-Life Score. Disease biomarkers included cerebrospinal fluid and serum levels of neurofilament light chain (NfL) and urinary p75 neurotrophin receptor.
RESULTS
IC14 was safe and well tolerated. No antidrug antibodies were detected. The drug target saturation of monocyte CD14 receptors was rapid and sustained through day 8. There was no significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, or Revised ALS-Specific Quality-of-Life Score following a single cycle of treatment. Cerebrospinal fluid NfL levels decreased in 6 of 9 patients sampled with declines of 15% to 40% between baseline (not significant [ns]) and day 8 in 3 patients. Serum NfL modestly decreased in 5 of 10 patients (ns) at day 8 and was sustained in 4 (4%-37%, ns) over 33 days of follow up.
CONCLUSION
IC14 quickly and durably saturated its target in all patients. This study demonstrated safety and tolerability in patients with amyotrophic lateral sclerosis. Even though only a single cycle of treatment was given, there were promising beneficial trends in the neurofilament light chain, a disease biomarker. The emerging understanding of the role of systemic inflammation in neurodegenerative diseases, and the potential for IC14 to serve as a safe, potent, and broad-spectrum inhibitor of immune dysregulation merits further clinical study.
CLINICAL TRIAL REGISTRATION
NCT03487263.
背景
本研究的主要目的是评估抗 CD14 单克隆抗体（IC14，atibuclimab）在肌萎缩侧索硬化症（ALS）患者中的安全性和耐受性。次要目的是评估其药代动力学、药效学以及对疾病状况和生物标志物的初步影响。
方法
这是一项开放标签、剂量递增的临床试验，3 例患者先静脉注射（IV）2mg/kg 的 IC14，随后每日 IV 输注 1mg/kg，连续 3 天（n=3），随后 7 例患者先 IV 输注 4mg/kg 的 IC14，随后每日 IV 输注 2mg/kg，连续 3 天（n=7）（NCT03487263）。采用修订版肌萎缩侧索硬化功能评定量表（ALSFRS-R）、用力肺活量（FVC）、嗅探鼻压力（SNIP）、爱丁堡认知和行为 ALS 筛查量表（ECAS）和修订版 ALS 特异性生活质量评分（ALSSQOL）评估疾病状况。疾病生物标志物包括脑脊液和血清中的神经丝轻链（NfL）以及尿 p75 神经生长因子受体。
结果
IC14 安全且耐受良好。未检测到抗药物抗体。单核细胞 CD14 受体的药物靶标饱和度在第 8 天仍保持快速和持续。单次治疗周期后，ALSFRS-R、FVC、SNIP 或 ALSSQOL 均无显著变化。9 例接受脑脊液样本检测的患者中，有 6 例患者的 NfL 水平在基线时（无显著差异[ns]）和第 8 天分别下降了 15%至 40%，3 例患者下降更显著。10 例接受血清样本检测的患者中有 5 例（ns）在第 8 天 NfL 略有下降，4 例（4%至 37%，ns）在 33 天的随访中持续下降。
结论
IC14 在所有患者中均快速且持久地达到了靶标饱和度。本研究在 ALS 患者中证实了安全性和耐受性。尽管仅给予了一个治疗周期，但在神经丝轻链（一种疾病生物标志物）中观察到了有希望的有益趋势。全身性炎症在神经退行性疾病中的作用的新认识，以及 IC14 作为一种安全、有效、广谱免疫调节抑制剂的潜力，值得进一步的临床研究。
临床试验注册
NCT03487263。
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