Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.
Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.
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DOI：
10.1016/j.jconrel.2020.10.011
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发表时间：
2021-01-10
期刊：
影响因子：
--
通讯作者：
Lai SK
中科院分区：
文献类型：
--
作者：
McSweeney MD;Shen L;DeWalle AC;Joiner JB;Ciociola EC;Raghuwanshi D;Macauley MS;Lai SK
针对聚乙二醇的免疫反应可导致聚乙二醇化药物的快速清除，并与严重不良事件(如输液反应和过敏反应)的风险增加有关。虽然特定的聚乙二醇化治疗药物可以诱导抗聚乙二醇抗体(APA)，但目前还没有容易部署的策略来减轻它们的负面影响。鉴于大量的聚乙二醇化治疗药物是FDA批准的或处于临床开发中，抑制APA诱导以确保患者使用聚乙二醇化药物的安全性和有效性的方法将是一种有价值的临床工具。我们之前的研究表明，在APA滴度较高的动物体内，注射无高分子量(MW)的聚乙二醇脂质体可以安全有效地恢复聚乙二醇脂质体的循环，而不会刺激额外的APA产生。在这里，我们探索了用游离的聚乙二醇脂质体或耐受性聚乙二醇化脂质体预防的有效性，以减少随后给予聚乙二醇化脂质体引起的急性呼吸暂停。令人惊讶的是，我们发现，单次注射游离聚乙二醇脂质体能够显著降低APA对聚乙二醇脂质体的反应达2个月之久；其效果与不同耐受性聚乙二醇脂质体的干预效果相当，而且常常超过。这些结果支持进一步研究游离聚乙二醇化预防作为一种策略，以改善APA对增敏聚乙二醇化治疗的反应。
Immune responses against polyethylene glycol (PEG) can lead to the rapid clearance of PEGylated drugs and are associated with increased risk of serious adverse events such as infusion reactions and anaphylaxis. Although select PEGylated therapeutics can induce anti-PEG antibodies (APA), there is currently no readily deployable strategy to mitigate their negative effects. Given the large number of PEGylated therapeutics that are either FDA-approved or in clinical development, methods that suppress APA induction to ensure the safety and efficacy of PEGylated drugs in patients would be a valuable clinical tool. We previously showed that infusion of high molecular weight (MW) free PEG can safely and effectively restore the circulation of PEG liposomes in animals with high pre-existing titers of APA, without stimulating additional APA production. Here, we explored the effectiveness of prophylaxis with free PEG or tolerogenic PEGylated liposomes in reducing APA induced by subsequently administered PEGylated liposomes. Surprisingly, we found that a single administration of free PEG alone was capable of markedly reducing the APA response to PEG-liposomes for ~2 months; the effectiveness was comparable to, and frequently exceeded, interventions with different tolerogenic PEG-liposomes. These results support further investigation of free PEG prophylaxis as a strategy to ameliorate the APA response to sensitizing PEGylated therapeutics.
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