Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina - Chapel Hill, North Carolina, USA.
Department of Chemistry, Department of Medical Microbiology and Immunology, University of Alberta, USA.
J Control Release. 2021 Jan 10;329:774-781. doi: 10.1016/j.jconrel.2020.10.011. Epub 2020 Oct 7.
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 as a strategy to reduce the amount of 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 investigations of free PEG prophylaxis as a potential strategy to ameliorate the APA response to sensitizing PEGylated therapeutics.
免疫反应针对聚乙二醇（PEG）可能导致 PEG 化药物的快速清除，并与输注反应和过敏反应等严重不良事件的风险增加相关。尽管某些 PEG 化治疗药物可以诱导抗 PEG 抗体（APA），但目前没有易于部署的策略来减轻其负面影响。鉴于大量已获得 FDA 批准或正在临床开发的 PEG 化治疗药物，抑制 APA 诱导以确保 PEG 化药物在患者中的安全性和疗效的方法将是一种有价值的临床工具。我们之前曾表明，输注高分子量（MW）游离 PEG 可以安全有效地恢复具有高预先存在的 APA 滴度的动物中 PEG 脂质体的循环，而不会刺激额外的 APA 产生。在这里，我们探讨了游离 PEG 或耐受型 PEG 化脂质体作为预防策略的有效性，以减少随后给予的 PEG 化脂质体诱导的 APA 量。令人惊讶的是，我们发现单次给予游离 PEG 本身就能够显著降低对 PEG-脂质体的 APA 反应持续约 2 个月；其有效性与不同耐受型 PEG 化脂质体的干预措施相当，并且经常超过。这些结果支持进一步研究游离 PEG 预防作为减轻致敏性 PEG 化治疗药物的 APA 反应的潜在策略。
