Journal article
Accelerated blood clearance and hypersensitivity by PEGylated liposomes containing TLR agonists
Department of Health Technology, Technical University of Denmark1
Center for Nanomedicine and Theranostics, Centers, Technical University of Denmark2
Biotherapeutic Engineering and Drug Targeting, Department of Health Technology, Technical University of Denmark3
Colloids & Biological Interfaces, Biotherapeutic Engineering and Drug Targeting, Department of Health Technology, Technical University of Denmark4
University of Copenhagen5
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.
Language: | English |
---|---|
Year: | 2022 |
Pages: | 337-344 |
ISSN: | 18734995 and 01683659 |
Types: | Journal article |
DOI: | 10.1016/j.jconrel.2021.12.033 |
ORCIDs: | 0000-0002-2706-5547 , Stavnsbjerg, Camilla , Christensen, Esben , Münter, Rasmus , Henriksen, Jonas R. , Hansen, Anders E. and Andresen, Thomas L. |
Anti-PEG antibodies Hypersensitivity Liposomes PEG PEGylated liposomes SDG 3 - Good Health and Well-being Systemic dosing TLRs Toll-like receptor agonists
Immunoglobulin M Nanoparticles Polyethylene Glycols Tissue Distribution