Forest Thomas, Xu Qiuwei, Kuruvilla Sabu, Vu Heather, Vlasakova Katerina, Glaab Warren E, Hines Cathy, Xun Song
1 Merck Research Laboratories, West Point, Pennsylvania, USA.
Toxicol Pathol. 2017 Jul;45(5):604-613. doi: 10.1177/0192623317714068. Epub 2017 Jul 4.
Conjugation with polyethylene glycol (PEG) is a strategy for improving the pharmaceutical properties of therapeutic proteins. In nonclinical studies of PEGylated compounds, microscopic tissue vacuolation is often observed, characterized ultrastructurally in this report by lysosomal distension. Although PEGylation-associated vacuolation appears to be of limited toxicologic concern when alternative therapies are limited, the risk-benefit considerations may be impacted by uncertainty about reversibility, lack of methods for monitoring PEG accumulation in vivo without biopsy, and the variability in tissues affected depending on species studied. We demonstrate the use of magnetic resonance spectroscopy (MRS) to measure PEG concentrations at multiple time points in vivo in the kidney with comparison to PEG concentrations ex vivo in body fluids and tissue extracts using nuclear magnetic resonance (NMR) spectroscopy. Furthermore, we demonstrate the use of these techniques to study distribution and elimination of PEG in a dog model of PEGylation-associated vacuolation. This report suggests that MRS could be further investigated as a feasible imaging-based method for monitoring PEG accumulation in a clinical setting in conjunction with NMR quantitation of PEG in plasma and urine.
与聚乙二醇（PEG）偶联是一种改善治疗性蛋白质药物性质的策略。在聚乙二醇化化合物的非临床研究中，经常观察到微观组织空泡化，本报告通过溶酶体扩张对其进行超微结构表征。尽管在替代疗法有限时，聚乙二醇化相关的空泡化似乎在毒理学方面的问题有限，但风险效益考量可能会受到可逆性不确定性、缺乏在不进行活检的情况下监测体内PEG积累的方法以及根据所研究物种不同而受影响组织存在变异性的影响。我们展示了使用磁共振波谱（MRS）在体内多个时间点测量肾脏中PEG浓度，并与使用核磁共振（NMR）波谱法测量体液和组织提取物中的体外PEG浓度进行比较。此外，我们展示了使用这些技术在聚乙二醇化相关空泡化的犬模型中研究PEG的分布和消除。本报告表明，结合血浆和尿液中PEG的NMR定量，MRS可作为一种可行的基于成像的方法在临床环境中进一步研究以监测PEG积累。
