Overcoming anti-PEG antibody mediated accelerated blood clearance of PEGylated liposomes by pre-infusion with high molecular weight free PEG

JOURNAL OF CONTROLLED RELEASE

卷:311

Article

McSweeney, Morgan D.¹  Price, Lauren S. L.²  Wessler, Timothy³  Ciociola, Elizabeth C.¹  Herity, Leah B.²  Piscitelli, Joseph A.²  DeWalle, Alexander C.¹  Harris, Taylor N.¹  Chan, Andy K. P.¹  Saw, Ran Sing¹  Hu, Peiqi⁴  Jennette, J. Charles⁴  Forest, M. Gregory³  Cao, Yanguang²  Montgomery, Stephanie A.^4,5  Zamboni, William C.²  Lai, Samuel K.^1,6,7 

[1] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacoengn & Mol Pharmaceut, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Dept Math, Chapel Hill, NC 27599 USA

[4] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA

[5] Univ N Carolina, Lineburger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[6] Univ N Carolina, UNC NCSU Joint Dept Biomed Engn, Chapel Hill, NC 27599 USA

[7] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA

关键词: Polyethylene glycol antibodies;    Anti-PEG antibodies;    PEGylation;    Polyethylene glycol;    Anti-drug antibodies;    Drug delivery;    Accelerated blood clearance;    Nanoparticles;   

DOI  :  10.1016/j.jconrel.2019.08.017

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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