1 Janssen R&D, LLC, Spring House, PA, USA.
2 Tox Path Specialists, LLC, Walkersville, MD, USA.
Int J Toxicol. 2019 May/Jun;38(3):173-182. doi: 10.1177/1091581819830980. Epub 2019 Mar 10.
Fulranumab, an anti-human nerve growth factor antibody, was evaluated in a series of nonclinical toxicology studies. No treatment effects were observed in adolescent cynomolgus monkeys in standard design, repeat-dose toxicology studies of up to 6 months. Adverse effects on the developing nervous system were observed in offspring of pregnant cynomolgus monkeys treated with fulranumab. Subsequent studies including detailed morphologic investigations of the nervous system did reveal fulranumab-related changes in adult cynomolgus monkeys; this article is focused on those findings. A single dose of ≥1 mg/kg fulranumab administered subcutaneously (SC) caused a decrease in neuron and sympathetic ganglion size (superior cervical ganglion), observed morphologically and stereologically, with a resulting appearance of increased glial cell density. Similar results were observed in repeat-dose (15 to 52 weeks) toxicity studies at ≤50 mg/kg/wk fulranumab SC. These effects recovered after a 3-month treatment-free period. Fulranumab did not cause any neuronal death, necrosis, apoptosis, or any apparent decrease in function of sympathetic neurons/ganglia at any time point examined. A no observed effect level (NOEL) was established at 0.25 mg/kg fulranumab SC every 4 weeks for 28 weeks.
富鲁单抗是一种抗人神经生长因子抗体，在一系列非临床毒理学研究中进行了评估。在长达 6 个月的标准设计、重复剂量毒理学研究中，未观察到青春期食蟹猴出现治疗作用。在接受富鲁单抗治疗的怀孕食蟹猴的后代中观察到对发育中神经系统的不良影响。随后的研究包括对神经系统进行详细的形态学研究，确实在成年食蟹猴中发现了与富鲁单抗相关的变化；本文重点介绍了这些发现。单次皮下（SC）给予≥1mg/kg 的富鲁单抗可导致神经元和交感神经节（颈上神经节）大小减小，通过形态学和体视学观察到，结果表现为神经胶质细胞密度增加。在≤50mg/kg/周富鲁单抗 SC 的重复剂量（15 至 52 周）毒性研究中观察到类似的结果。在 3 个月的无治疗期后，这些影响得到恢复。在任何检查时间点，富鲁单抗均未引起神经元死亡、坏死、凋亡，或交感神经元/神经节功能明显下降。富鲁单抗 SC 每 4 周给药 0.25mg/kg，28 周的无观察到不良效应水平（NOEL）为 0.25mg/kg。
