Jintrolong®是一种长效聚乙二醇化重组人生长激素(PEG-rhGH),可在小儿生长激素缺乏症(PGHD)患者中每周注射一次。虽然治疗性蛋白质的PEG修饰通常被认为是安全的,对于长期暴露于含PEG的疗法的组织中不良空泡化的可能性仍然存在担忧,特别是在儿童中。我们通过检查脑脉络丛(CP)中的空泡,评估了Jintrolong®在食蟹猴中的安全性,并报告了从PGHD儿童获得的长期临床安全性数据。在以0.3、1或3mg/kg/周的剂量施用52周后评估Jintrolong®的毒性。动物中CP的空泡化水平是剂量依赖性的,并且在104或157周的恢复期后至少部分可逆。CP上皮的空泡形成未导致明显的亚细胞结构或细胞功能异常。与PGHD患者中Jintrolong®的0.2mg/kg/周的临床剂量相比,在猴子中暴露于NOAEL3mg/kg/周的安全系数大于120.5,在猴子中诱导空泡化的预测最小剂量相当于人类的1.29mg/kg/周,比临床剂量高6.45倍。还分析了Jintrolong®临床试验中获得的安全性数据,其中包括III期(360名患者),26周治疗的IV期(3,000名患者),以及持续3年治疗的随访研究。Jintrolong®组与每日rhGH对照组(无PEG)之间的不良反应发生率无统计学差异,在临床治疗剂量为0.2mg/kg/周的Jintrolong®组中未观察到新的不良反应(AE)。
Jintrolong® is a long-acting PEGylated recombinant human growth hormone (PEG-rhGH) developed for weekly injection in patients with pediatric growth hormone deficiency (PGHD). Although PEG modification of therapeutic proteins is generally considered safe, concerns persist about the potential for adverse
vacuolation in tissues with long-term exposure to PEG-included therapies, particularly in children. We assessed the safety of Jintrolong® in cynomolgus monkeys with an examination of
vacuolation in the brain choroid plexus (CP) and reported long-term clinical safety data obtained from children with PGHD. The toxicity of Jintrolong® was assessed following the 52-week administration with doses at 0.3, 1, or 3 mg/kg/week. The levels of
vacuolation of CP in animals were dose-dependent and at least partially reversible after a 104- or 157-week recovery period.
Vacuolation in the CP epithelium did not lead to obvious subcellular structural or cell functional abnormalities. Compared with the clinical dose of 0.2 mg/kg/week Jintrolong® in PGHD patients, exposure in monkeys under NOAEL 3 mg/kg/week exhibited safety margins greater than 120.5, the predicted minimum dose to induce
vacuolation in monkeys is equivalent to 1.29 mg/kg/week in humans, which is 6.45-fold higher than the clinical dose. The safety data acquired in clinical trials for Jintrolong® were also analyzed, which included phase III (360 patients), phase IV (3,000 patients) of 26-week treatment, and a follow-up study with treatment lasting for 3 years. There was no statistically significant difference in the incidence of adverse reactions between the Jintrolong® group and the daily rhGH control group (no PEG), and no new adverse effects (AE) were observed in the Jintrolong® group at the clinical therapeutic dose of 0.2 mg/kg/week.