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High MW polyethylene glycol prolongs circulation of pegloticase in mice with anti-PEG antibodies
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2021-09-02 , DOI: 10.1016/j.jconrel.2021.08.051
Anne M Talkington 1 , Morgan D McSweeney 2 , Tao Zhang 3 , Zibo Li 4 , Andrew C Nyborg 5 , Brian LaMoreaux 5 , Eric W Livingston 6 , Jonathan E Frank 6 , Hong Yuan 4 , Samuel K Lai 7
Affiliation  

Pegloticase is an enzyme used to reduce serum uric acid levels in patients with chronic, treatment-refractory gout. Clinically, about 40% of patients develop high titers of anti-PEG antibodies (APA) after initial treatment, which in turn quickly eliminate subsequent doses of pegloticase from the systemic circulation and render the treatment ineffective. We previously found that pre-infusion with high MW free PEG (40 kDa) can serve as a decoy to saturate circulating APA, preventing binding to a subsequently administered dose of PEG-liposomes and restoring their prolonged circulation in mice, without any detectible toxicity. Here, we investigated the use of 40 kDa free PEG to restore the circulation of radio-labeled pegloticase in mice using longitudinal Positron Emission Tomography (PET) imaging over 4 days. Mice injected with pegloticase developed appreciable APA titers by Day 9, which further increased through Day 14. Compared to naïve mice, mice with pegloticase-induced APA rapidly cleared 89Zr-labeled pegloticase, with ~75% lower pegloticase concentrations in the circulation at four hours after treatment. The 96-h AUC in APA+ mice was less than 30% of the AUC in naïve mice. In contrast, pre-infusion of free PEG into PEG-sensitized mice restored the AUC of pegloticase to ~80% of that seen in naïve mice, resulting in a similar biodistribution to pegloticase in naïve mice over time. These results suggest that pre-infusion of free PEG may be a promising strategy to enable the safe and efficacious use of pegloticase and other PEGylated drugs in patients that have previously failed therapy due to induced APA.



中文翻译:

高分子量聚乙二醇可延长具有抗 PEG 抗体的小鼠中聚乙二醇化酶的循环

Pegloticase 是一种酶,用于降低慢性难治性痛风患者的血清尿酸水平。临床上,大约 40% 的患者在初始治疗后会产生高滴度的抗 PEG 抗体 (APA),这反过来又会迅速从体循环中消除后续剂量的聚乙二醇化酶并使治疗无效。我们之前发现,用高 MW 游离 PEG (40 kDa) 预输液可以作为诱饵使循环 APA 饱和,防止与随后施用的 PEG-脂质体结合并恢复它们在小鼠体内的延长循环,而没有任何可检测到的毒性。在这里,我们在 4 天内使用纵向正电子发射断层扫描 (PET) 成像研究了使用 40 kDa 游离 PEG 来恢复小鼠体内放射性标记的聚乙二醇化酶的循环。89 Zr 标记的聚乙二醇化酶,治疗后 4 小时循环中的聚乙二醇化酶浓度降低约 75%。APA+ 小鼠的 96 小时 AUC 小于幼稚小鼠 AUC 的 30%。相比之下,将游离 PEG 预注入 PEG 致敏小鼠中,可将聚乙二醇化酶的 AUC 恢复到在幼稚小鼠中观察到的约 80%,从而随着时间的推移在幼稚小鼠中产生与聚乙二醇化酶相似的生物分布。这些结果表明,游离 PEG 的预输注可能是一种有前途的策略,可以使先前因诱导 APA 治疗失败的患者安全有效地使用聚乙二醇化酶和其他聚乙二醇化药物。

更新日期:2021-09-19
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