School of Biomedical Sciences, University of Queensland, St Lucia, QLD 4072, Australia.
Mol Pharm. 2023 Jul 3;20(7):3494-3504. doi: 10.1021/acs.molpharmaceut.3c00104. Epub 2023 May 31.
PEGylated lipid nanoparticle-based Covid-19 vaccines, including Pfizer's BNT162b2 and Moderna's mRNA-1273, have been shown to stimulate variable anti-PEG antibody production in humans. Anti-PEG antibodies have the potential to accelerate the plasma clearance of PEGylated therapeutics, such as PEGylated liposomes and proteins, and compromise their therapeutic efficacy. However, it is not yet clear whether antibody titers produced by PEGylated Covid-19 vaccines significantly affect the clearance of PEGylated therapeutics. This study examined how anti-PEG IgM levels affect the pharmacokinetics of PEGylated liposomal doxorubicin (PLD) and compared the immunogenicity of a lipid nanoparticle formulation of linear DNA (DNA-LNP) to standard PEG-HSPC liposomes. DNA-LNP was prepared using the same composition and approach as Pfizer's BNT162b2, except linear double-stranded DNA was used as the genetic material. PEGylated HSPC-based liposomes were formulated using the lipid rehydration and extrusion method. Nanoparticles were dosed IM to rats at 0.005-0.5 mg lipid/kg body weight 1 week before evaluating the plasma pharmacokinetics of clinically relevant doses of PLD (1 mg/kg, IV) or PEGylated interferon α2a (Pegasys, 5 μg/kg, SC). Plasma PEG IgM was compared between pre- and 1-week post-dose blood samples. The results showed that anti-PEG IgM production increased with increasing PEG-HSPC liposome dose and that IgM significantly correlated with the plasma half-life, clearance, volume of distribution, and area under the curve of a subsequent dose of PLD. The plasma exposure of Pegasys was also significantly reduced after initial delivery of 0.005 mg/ml PEG-HSPC liposome. However, a single 0.05 mg/kg IM dose of DNA-LNP did not significantly elevate PEG IgM and did not alter the IV pharmacokinetics of PLD. These data showed that PEGylated Covid-19 vaccines are less immunogenic compared to standard PEGylated HSPC liposomes and that there is an antibody threshold for accelerating the clearance of PEGylated therapeutics.
基于聚乙二醇化脂质纳米颗粒的 COVID-19 疫苗，包括辉瑞的 BNT162b2 和 Moderna 的 mRNA-1273，已被证明可在人体中刺激可变的抗聚乙二醇抗体产生。抗聚乙二醇抗体有可能加速聚乙二醇化治疗剂（如聚乙二醇化脂质体和蛋白质）的血浆清除，并损害其治疗效果。然而，目前尚不清楚 COVID-19 疫苗产生的抗体滴度是否会显著影响聚乙二醇化治疗剂的清除。本研究检查了抗聚乙二醇 IgM 水平如何影响聚乙二醇化脂质体阿霉素（PLD）的药代动力学，并比较了线性 DNA 的脂质纳米颗粒制剂（DNA-LNP）与标准聚乙二醇化 HSPC 脂质体的免疫原性。DNA-LNP 是使用与辉瑞的 BNT162b2 相同的组成和方法制备的，只是使用线性双链 DNA 作为遗传物质。基于聚乙二醇化 HSPC 的脂质体是通过脂质再水合和挤出方法制备的。在评估临床相关剂量 PLD（1mg/kg，IV）或聚乙二醇化干扰素 α2a（Pegasys，5μg/kg，SC）的血浆药代动力学之前，将纳米颗粒以 0.005-0.5mg 脂质/kg 体重 IM 给药至大鼠。比较了预给药和 1 周后给药血样之间的血浆 PEG IgM。结果表明，抗聚乙二醇 IgM 产量随聚乙二醇 HSPC 脂质体剂量的增加而增加，并且 IgM 与 PLD 后续剂量的血浆半衰期、清除率、分布容积和曲线下面积显著相关。在初始给予 0.005mg/ml PEG-HSPC 脂质体后，Pegasys 的血浆暴露也显著降低。然而，单次 0.05mg/kg IM 剂量的 DNA-LNP 不会显著升高 PEG IgM，也不会改变 PLD 的 IV 药代动力学。这些数据表明，与标准聚乙二醇化 HSPC 脂质体相比，基于聚乙二醇化的 COVID-19 疫苗的免疫原性较低，并且存在加速聚乙二醇化治疗剂清除的抗体阈值。
