High Molecular Weight Polyethylene Glycol Cellular Distribution and PEG-associated Cytoplasmic Vacuolation Is Molecular Weight Dependent and Does Not Require Conjugation to Proteins

Toxicologic Pathology - Tập 41 Số 7 - Trang 970-983 - 2013
Daniel G. Rudmann1, James T. Alston1, Jeffrey C. Hanson1, Shawn M. Heidel2
1#N#1Translational Sciences and Investigative Pathology, Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA
2#N#2Preclinical Services, Covance Inc., Greenfield, Indiana, USA

Tóm tắt

Conjugation of therapeutic proteins with high molecular weight polyethylene glycols (HMW PEGs) is used to extend the half-life of biologics. To evaluate the effects of HMW PEGs in animals, we used an immunohistochemical procedure to study the tissue distribution and toxicity of unconjugated HMW PEGs in rats given 100 mg/kg 10KPEG, 20KPEG, or 40KPEG intravenously. Both the PEG cellular distribution and the histology were different between groups. In 10KPEG and 20KPEG groups, PEG immunoreactivity was most prominent in the renal tubule epithelium and in alveolar macrophages and hepatic Kupffer cells and cellular vacuolation was absent. In contrast, rats given 40KPEG had strong PEG immunoreactivity in splenic subcapsular red pulp macrophages, renal interstitial macrophages, and choroid plexus epithelial cells that was frequently associated with cytoplasmic vacuolation. While the vacuolation appeared to be an adaptive response, there was focal renal tubular epithelial degeneration associated with strong PEG immunoreactivity in one rat given 40KPEG. These data indicate that both the tissue distribution and the vacuolation observed with unconjugated HMW PEGs are markedly influenced by the molecular weight of the PEG and that when vacuolation is observed it is likely an adaptive change that is associated with PEG cytoplasmic immunoreactivity.

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Toxicologic Pathology

Tập 41 Số 7

970-983

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