Accelerated blood clearance and hypersensitivity by PEGylated liposomes containing TLR agonists

Camilla Stavnsbjerg, Esben Christensen, Rasmus Münter, Jonas R Henriksen, Matthias Fach, Ladan Parhamifar, Camilla Christensen, Andreas Kjaer, Anders E Hansen, Thomas L Andresen

25 Citations (Scopus)


Systemic administration of toll-like receptor (TLR) agonists have demonstrated impressive preclinical results as an anti-cancer therapy due to their potent innate immune-stimulatory properties. The clinical advancement has, however, been hindered by severe adverse effects due to systemic activation of the immune system. Liposomal drug delivery systems may modify biodistribution, cellular uptake, and extend blood circulation, and thus, potentially enable systemic administration of TLR agonists at therapeutic doses. In this study, we investigated potential barriers for the administration of TLR agonists formulated in polyethylene glycosylated (PEGylated) liposomes with regards to liposome formulation, TLR agonist, administration route, administration schedule, biodistribution, blood clearance, and anti-PEG antibodies. We found that administration of TLR agonists formulated in PEGylated liposomes led to high anti-PEG antibody titers, which upon multiple intravenous administrations, resulted in accelerated blood clearance and acute hypersensitivity reactions. The latter was found to be associated with anti-PEG IgG antibody and not anti-PEG IgM antibody opsonization. This study highlights the need to carefully design and evaluate nanoparticle delivery systems for immunotherapy as anti-nanoparticle immune responses may challenge the therapeutic application.

Original languageEnglish
JournalJournal of Controlled Release
Pages (from-to)337-344
Number of pages8
Publication statusPublished - Feb 2022


  • Anti-PEG antibodies
  • Hypersensitivity
  • Liposomes
  • PEG
  • PEGylated liposomes
  • Systemic dosing
  • TLRs
  • Toll-like receptor agonists


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