Program in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC, USA.
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
J Control Release. 2021 Oct 10;338:804-812. doi: 10.1016/j.jconrel.2021.08.051. Epub 2021 Sep 2.
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 Zr-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.
培戈洛酶是一种用于降低慢性、治疗抵抗性痛风患者血清尿酸水平的酶。临床上，约 40%的患者在初始治疗后会产生高滴度的抗-PEG 抗体（APA），这反过来又会迅速将后续剂量的培戈洛酶从全身循环中清除，使治疗无效。我们之前发现，在输注前预先输注高分子量游离 PEG（40 kDa）可以作为诱饵，使循环中的 APA 饱和，防止其与随后给予的 PEG-脂质体结合，并恢复其在小鼠中的延长循环，而没有任何可检测的毒性。在这里，我们通过纵向正电子发射断层扫描（PET）成像在 4 天内研究了使用 40 kDa 游离 PEG 来恢复小鼠中放射性标记的培戈洛酶循环的用途。注射培戈洛酶的小鼠在第 9 天产生了可观的 APA 滴度，并且通过第 14 天进一步增加。与未致敏小鼠相比，具有培戈洛酶诱导的 APA 的小鼠迅速清除 Zr 标记的培戈洛酶，在治疗后 4 小时，循环中的培戈洛酶浓度降低了约 75%。在 APA+小鼠中，96 小时 AUC 小于未致敏小鼠的 30%。相比之下，在 PEG 致敏小鼠中预先输注游离 PEG 将培戈洛酶的 AUC 恢复到未致敏小鼠的约 80%，从而在一段时间内使培戈洛酶在未致敏小鼠中的生物分布与培戈洛酶相似。这些结果表明，预先输注游离 PEG 可能是一种很有前途的策略，可以使以前因诱导 APA 而治疗失败的患者安全有效地使用培戈洛酶和其他聚乙二醇化药物。
