期刊
JOURNAL OF CONTROLLED RELEASE
卷 311, 期 -, 页码 138-146出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2019.08.017
关键词
Polyethylene glycol antibodies; Anti-PEG antibodies; PEGylation; Polyethylene glycol; Anti-drug antibodies; Drug delivery; Accelerated blood clearance; Nanoparticles
资金
- National Science Foundation Graduate Research Fellowship [DGE-1650116]
- David and Lucile Packard Foundation [2013-39274]
- National Institutes of Health [R01 HL141934, R35 GM119661]
- UNC Research Opportunities Initiative grant in Pharmacoengineering
- National Science Foundation [DMS-1462992, DMS-1412844, DMS-1517274, DMS-1664645]
Antibodies that specifically bind polyethylene glycol (PEG), i.e. anti-PEG antibodies (APA), are associated with reduced efficacy and increased risk of serious adverse events for several PEGylated therapeutics. Here, we explored the concept of using free PEG molecules to saturate circulating APA. Surprisingly, we found that 40 kDa free PEG effectively restored the prolonged circulation of PEGylated liposomes in the presence of high titers of pre-existing APA for at least 48 h in mice. In contrast, lower molecular weight free PEG (<= 10 kDa) failed to restore circulation beyond a few hours. These in vivo results were consistent with estimates from a minimal physiologically based pharmacokinetic model. Importantly, the infusion of free PEG appeared to be safe in mice previously sensitized by injection of PEGylated liposomes, and free PEG did not elicit excess APA production even in mice with pre-existing adaptive immunity against PEG. Our results support further investigation of high molecular weight free PEG as a potential method to control and overcome high titers of APA, restoring the prolonged circulation of PEGylated liposomes and possibly other PEGylated therapeutics.
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