Division of Molecular Pharmaceutics, Eshelman School of Pharmacy; ‡Lineberger Cancer Center, Biostatistics Shared Resource; §UNC/NCSU Joint Department of Biomedical Engineering; ∥Department of Microbiology & Immunology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Anal Chem. 2016 Dec 6;88(23):11804-11812. doi: 10.1021/acs.analchem.6b03437. Epub 2016 Nov 16.
Circulating antibodies (Ab) that specifically bind polyethylene glycol (PEG), a biocompatible polymer routinely used in protein and nanoparticle therapeutics, have been associated with reduced efficacy of and/or adverse reactions to therapeutics modified with or containing PEG. Unlike most antidrug antibodies that are induced following initial drug dosing, anti-PEG Ab can be found in treatment-naïve individuals (i.e., individuals who have never undergone treatment with PEGylated drugs but most likely have been exposed to PEG through other means). Unfortunately, the true prevalence, quantitative levels, and Ab isotype of pre-existing anti-PEG Ab remain poorly understood. Here, using rigorously validated competitive ELISAs with engineered chimeric anti-PEG monoclonal Ab standards, we quantified the levels of anti-PEG IgM and different subclasses of anti-PEG IgG (IgG1-4) in both contemporary and historical human samples. We unexpectedly found, with 90% confidence, detectable levels of anti-PEG Ab in ∼72% of the contemporary specimens (18% IgG, 25% IgM, 30% both IgG and IgM). The vast majority of these samples contained low levels of anti-PEG Ab, with only ∼7% and ∼1% of all specimens possessing anti-PEG IgG and IgM in excess of 500 ng/mL, respectively. IgG2 was the predominant anti-PEG IgG subclass. Anti-PEG Ab's were also observed in ∼56% of serum samples collected during 1970-1999 (20% IgG, 19% IgM, and 16% both IgG and IgM), suggesting that the presence of PEG-specific antibodies may be a longstanding phenomenon. Anti-PEG IgG levels demonstrated correlation with patient age, but not with gender or race. The widespread prevalence of pre-existing anti-PEG Ab, coupled with high Ab levels in a subset of the population, underscores the potential importance of screening patients for anti-PEG Ab levels prior to administration of therapeutics containing PEG.
循环抗体（Ab）特异性结合聚乙二醇（PEG），PEG 是一种生物相容性聚合物，常用于蛋白质和纳米颗粒治疗药物中，与用 PEG 修饰或含有 PEG 的治疗药物的疗效降低和/或不良反应有关。与大多数在初次药物给药后诱导的抗药物抗体不同，抗-PEG Ab 可在未经治疗的个体中发现（即，从未接受过 PEG 化药物治疗但很可能通过其他方式接触过 PEG 的个体）。不幸的是，预先存在的抗-PEG Ab 的真实流行率、定量水平和 Ab 同种型仍知之甚少。在这里，我们使用经过严格验证的竞争 ELISA ，使用工程化的嵌合抗-PEG 单克隆 Ab 标准品，定量测定了当代和历史人类样本中抗-PEG IgM 和不同亚类抗-PEG IgG（IgG1-4）的水平。我们出人意料地发现，在 90%置信度下，在大约 72%的当代样本中可检测到抗-PEG Ab 的水平（18%IgG、25%IgM、30%IgG 和 IgM）。这些样本中的绝大多数都含有低水平的抗-PEG Ab，只有大约 7%和大约 1%的所有样本中 IgG 和 IgM 的抗-PEG Ab 超过 500ng/ml。IgG2 是主要的抗-PEG IgG 亚类。在 1970 年至 1999 年收集的大约 56%的血清样本中也观察到抗-PEG Ab（20%IgG、19%IgM 和 16%IgG 和 IgM），这表明 PEG 特异性抗体的存在可能是一个长期存在的现象。抗-PEG IgG 水平与患者年龄相关，但与性别或种族无关。预先存在的抗-PEG Ab 的广泛流行率，加上一部分人群中高 Ab 水平，突出表明在给予含有 PEG 的治疗药物之前，筛选患者的抗-PEG Ab 水平可能非常重要。
