Impact of Pre-Existing or Induced Anti-PEG IgM on the Pharmacokinetics of Peginterferon Alfa-2a (Pegasys) in Mice.,Molecular Pharmaceutics

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Impact of Pre-Existing or Induced Anti-PEG IgM on the Pharmacokinetics of Peginterferon Alfa-2a (Pegasys) in Mice.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-06-10 , DOI: 10.1021/acs.molpharmaceut.0c00366
Nehal E Elsadek ₁ , Eri Hondo ₁ , Taro Shimizu ₁ , Haruka Takata ₁ , Amr S Abu Lila _{2,

3} , Sherif E Emam _{1,

2} , Hidenori Ando ₁ , Yu Ishima ₁ , Tatsuhiro Ishida ₁

Affiliation

PEGylation had been used successfully to improve the circulation half-lives and some physicochemical properties of protein therapeutics. However, anti-polyethylene glycol (anti-PEG) antibodies, either pre-existing or treatment-induced, can negatively affect the pharmacokinetics and pharmacological efficacy of PEGylated proteins. We have examined anti-PEG immune responses in mice for peginterferon alfa-2a (Pegasys), a clinically approved PEGylated protein therapeutic, at both the recommended dose (equivalent to 3 μg/kg in mice) and at higher doses (150 μg/kg) for single or repeated subcutaneous (s.c.) administrations. The effect of treatment-induced anti-PEG IgM on serum concentrations of Pegasys, following repeated administrations, was evaluated. In addition, the effect of pre-existing anti-PEG IgM elicited by a different PEGylated protein, PEG-OVA, on the systemic clearance of Pegasys, was investigated. At a s.c. dose of 3 μg/kg, single injections of Pegasys barely elicited anti-PEG immune responses. Four repeated doses of 150 μg/kg Pegasys elicited anti-PEG IgM production, depending on dose frequency, and triggered the rapid clearance of subsequent doses. In addition, anti-PEG-IgM produced in response to prior administration of PEG-OVA caused a rapid blood clearance of Pegasys. Our results, therefore, underscore the importance of screening for both pre-existing and treatment-induced anti-PEG antibodies in patients prior to and during treatment with PEGylated protein drugs.

中文翻译：

预先存在或诱导的抗PEG IgM对Peginterferon Alfa-2a（Pegasys）在小鼠体内药代动力学的影响。

聚乙二醇化已成功地用于改善蛋白质治疗剂的循环半衰期和某些理化特性。但是，已存在或由治疗诱导的抗聚乙二醇（anti-PEG）抗体可能会对PEG化蛋白的药代动力学和药理效力产生负面影响。我们以推荐剂量（等效于小鼠3μg/ kg）和更高剂量（150μg/ kg）对peginterferon alfa-2a（Pegasys）（一种临床批准的PEG化蛋白治疗剂）的小鼠进行了抗PEG免疫反应研究）用于单次或重复皮下（sc）给药。反复给药后，评估了治疗诱导的抗PEG IgM对Pegasys血清浓度的影响。此外，预先存在的抗PEG IgM由不同的PEG化蛋白引起的影响，研究了PEG-OVA对Pegasys的全身清除作用。在皮下剂量为3μg/ kg时，单次注射Pegasys几乎不会引起抗PEG免疫反应。取决于剂量频率，四次重复剂量150μg/ kg的Pegasys引起抗PEG IgM的产生，并触发了随后剂量的快速清除。另外，响应于先前施用PEG-OVA而产生的抗PEG-IgM引起Pegasys的快速血液清除。因此，我们的结果强调了在用PEG化蛋白药物治疗之前和治疗期间对患者既存抗体和治疗诱导的抗PEG抗体进行筛选的重要性。取决于剂量频率，四次重复剂量150μg/ kg的Pegasys引起抗PEG IgM的产生，并触发了随后剂量的快速清除。另外，响应于先前施用PEG-OVA而产生的抗PEG-IgM引起Pegasys的快速血液清除。因此，我们的结果强调了在用PEG化蛋白药物治疗之前和治疗期间对患者既存抗体和治疗诱导的抗PEG抗体进行筛选的重要性。取决于剂量频率，四次重复剂量150μg/ kg的Pegasys引起抗PEG IgM的产生，并触发了随后剂量的快速清除。另外，响应于先前施用PEG-OVA而产生的抗PEG-IgM引起Pegasys的快速血液清除。因此，我们的结果强调了在用PEG化蛋白药物治疗之前和治疗期间对患者既存抗体和治疗诱导的抗PEG抗体进行筛选的重要性。

更新日期：2020-08-03

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