Evaluation of the Effects of Tanezumab, a Monoclonal Antibody Against Nerve Growth Factor, on the Sympathetic Nervous System in Adult Cynomolgus Monkeys (Macaca fascicularis): A Stereologic, Histomorphologic, and Cardiofunctional Assessment
Evaluation of the Effects of Tanezumab, a Monoclonal Antibody Against Nerve Growth Factor, on the Sympathetic Nervous System in Adult Cynomolgus Monkeys (Macaca fascicularis): A Stereologic, Histomorphologic, and Cardiofunctional Assessment
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DOI：
10.1093/toxsci/kfx089
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发表时间：
2017-08-01
影响因子：
3.8
通讯作者：
Zorbas, Mark
中科院分区：
文献类型：
--
作者：
Belanger, Patrice;Butler, Paul;Zorbas, Mark
Tanezumab 是一种针对神经生长因子的人源化单克隆抗体，正在开发用于治疗慢性疼痛。三项非临床研究评估了临床相关剂量和超治疗剂量的 tanezumab 对成年非人灵长类动物交感神经系统 (SNS) 的影响。研究 1 评估了皮下注射 (SC) tanezumab（每 8 周 1.2 mg/kg [Q8W]）对食蟹猴 SNS 的潜在影响，持续 3 或 6 个月，以及在非给药/恢复期内任何影响的可逆性或持续性。研究 2 评估了单次 SC tanezumab 注射（1.2 mg/kg）后是否会立即发生神经元细胞死亡。这两项研究的评估包括对颈上神经节和颈胸神经节神经元细胞死亡和形态的评估。研究 3 评估了 6 个月内 SC tanezumab（1.2 mg/kg Q8W 和 30 mg/kg/周）对心血管功能交感神经控制的影响。 Tanezumab 暴露与交感神经节的立体学变化相关，包括神经节体积变小，平均神经元大小/面积变小，从 2 周开始，到 1 个月达到最大水平，6 个月内没有进一步进展。这些变化与临床体征无关，在 tanezumab 停药后完全逆转，并且不被认为是不利的。 Tanezumab 对心血管功能的交感神经控制没有不良影响。这些数据支持以下结论：给予 tanezumab 长达 6 个月对 SNS 形态或功能没有不利影响，并且不会导致成年非人灵长类动物的神经元细胞死亡。
Tanezumab, a humanized monoclonal antibody against nerve growth factor is in development for treatment of chronic pain. Three nonclinical studies assessed effects of clinically relevant and supratherapeutic doses of tanezumab on the sympathetic nervous system (SNS) of adult nonhuman primates. Study 1 evaluated potential effects of subcutaneous (SC) tanezumab (1.2 mg/kg every 8 weeks [Q8W]) on SNS in cynomolgus monkeys for 3 or 6 months and reversibility or persistence of any effects through a nondosing/recovery period. Study 2 evaluated whether neuronal cell death occurs shortly after a single SC tanezumab injection (1.2 mg/kg). Assessments for these two studies included evaluations of superior cervical and cervicothoracic ganglia for neuronal cell death and morphology. Study 3 evaluated effects of SC tanezumab (1.2 mg/kg Q8W and 30 mg/kg/week) over 6 months on sympathetic control of cardiovascular function. Tanezumab exposure was associated with stereologic changes in sympathetic ganglia, including smaller ganglion volume, and smaller average neuron size/area beginning at 2 weeks and reaching maximal levels by 1 month with no further progression through 6 months. These changes were not associated with clinical signs, completely reversed upon tanezumab withdrawal, and were not considered adverse. Tanezumab had no adverse effects on sympathetic control of cardiovascular function. These data support the conclusion that tanezumab administration for up to 6 months has no adverse effects on SNS morphology or function and does not cause neuronal cell death in adult nonhuman primates.