(raw data) Overcoming anti-PEG antibody mediated accelerated blood clearance of PEGylated liposomes by pre-infusion with high molecular weight free PEG

Antibodies that specifically bind polyethylene glycol (PEG), i.e. anti-PEG antibodies (APA), are associated with reduced efficacy and increased risk of serious adverse events for several PEGylated therapeutics. Here, we explored the concept of using free PEG molecules to saturate circulating APA. Surprisingly, we found that 40 kDa free PEG effectively restored the prolonged circulation of PEGylated liposomes in the presence of high titers of pre-existing APA for at least 48 hours in mice. In contrast, lower molecular weight free PEG (≤10 kDa) failed to restore circulation beyond a few hours. These in vivo results were consistent with estimates from a minimal physiologically based pharmacokinetic model. Our results support further investigation of high molecular weight free PEG as a potential method to control and overcome high titers of APA, restoring the prolonged circulation of PEGylated liposomes and possibly other PEGylated therapeutics. The dataset uploaded here gives individual mouse-level concentrations of PEGylated liposome doxorubicin (PLD) in blood and organs of elimination. We tested the PK of PLD in naive mice and mice with low (3 ug dose) or high (30 ug dose) APA. We also tested whether administering various sizes of free PEG (10/20/40 kDa) could restore the long-lasting PK of PLD even in mice that received a high dose of APA. The first tab has descriptions of the study conditions tested in each phase (e.g. what size/dose of free PEG was administered to animals in that experiment)

特异性结合聚乙二醇（polyethylene glycol, PEG）的抗体，即抗PEG抗体（anti-PEG antibodies, APA），与多种聚乙二醇化治疗药物的疗效降低及严重不良事件风险升高相关。本研究围绕利用游离PEG分子饱和循环中APA的思路展开探索。令人意外的是，我们在小鼠实验中发现，当体内存在高滴度预存APA时，40 kDa游离PEG可有效恢复聚乙二醇化脂质体的延长循环时长，该效果至少可维持48小时。相较而言，低分子量游离PEG（≤10 kDa）仅能在数小时内恢复循环效果，无法维持更久的时长。上述体内实验结果与基于最小生理药代动力学模型的估算结果相一致。本研究结果支持进一步探究高分子量游离PEG作为调控并克服高滴度APA的潜在手段，以恢复聚乙二醇化脂质体乃至其他聚乙二醇化治疗药物的延长循环特性。本次上传的数据集包含了小鼠个体水平的聚乙二醇化脂质体阿霉素（PEGylated liposome doxorubicin, PLD）在血液及清除器官中的浓度数据。我们分别检测了未致敏小鼠、低剂量（3 μg）或高剂量（30 μg）APA小鼠体内PLD的药代动力学（pharmacokinetic, PK）特征。同时，我们还测试了在给予高剂量APA的小鼠中，输注不同分子量的游离PEG（10/20/40 kDa）是否能够恢复PLD的长效药代动力学特性。数据集的第一个工作表包含了各实验阶段所测试的研究条件说明（例如该实验中向动物给予的游离PEG分子量与剂量）。