label: url

en: Impact of pre-existing anti-polyethylene glycol (PEG) IgM on biodistribution and humoral response of intramuscularly administered PEGylated mRNA loaded lipid nanoparticle

en: With the approval of mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), lipid nanoparticles (LNP) have emerged as a powerful tool for nucleic acid delivery. Modification of LNP with polyethylene glycol (PEG)-lipids contributes to their in vitro and in vivo stability by reducing aggregation of the particles. Despite the general acknowledgement of the low immunogenicity of PEG, there are numerous reports of the occurrence of anti-PEG antibodies in the blood of healthy individuals. Furthermore, there are reports that pre-existing anti-PEG IgM antibodies attenuated the efficacy of PEG-modified drugs administered systemically. Skeletal muscles, the administration site for mRNA vaccines, are highly vascularized by a network of blood vessels to provide them with nutrients and oxygen. Since skeletal muscles can contain circulating anti-PEG antibodies or the administered mRNA-LNP extravasate into bloodstream, the purpose of this study was to evaluate the effects of pre-existing anti-PEG IgM on the protein translation, biodistribution, and humoral responses to mRNA-loaded LNP (mRNA-LNP) administered intramuscularly (i.m.) in mice. We found that the presence of anti-PEG IgM in blood has only a minor effect on the translation and distribution of mRNA-LNP in the localized muscle area where the mRNA-LNP were administered. Circulating anti-PEG IgM did not increase the total accumulation of mRNA-LNP in the liver, but did markedly diminish its protein translation because the mRNA-LNP were delivered primarily to Kupffer cells rather than to hepatocytes. Binding of anti-PEG IgM to mRNA-LNP, and subsequent complement activation, suppressed mRNA translation loaded in LNP in the liver. Repeated intramuscular injections of SARS-CoV-2 Spike protein mRNA-LNP elicited a robust immune response. Our results indicate that the presence of circulating anti-PEG IgM does not interfere with the efficiency of mRNA vaccines administered i.m. in mice. We can speculate that non-specific translation of mRNA vaccines in somatic cells may be inhibited in vivo by circulating anti-PEG IgM, reducing adverse effects such as hepatitis and myocarditis that are caused by immune responses against translated antigen proteins.

en: Journal of Controlled Release

ja: Journal of Controlled Release


en: Incorporating gangliosides into PEGylated cationic liposomes that complexed DNA attenuates anti-PEG antibody production, but not anti-DNA antibody production in mice

en: Gangliosides (glycosphingolipids) reduce antibody production by inhibiting B-cell receptor (BCR) signaling. We have shown that a copresentation of gangliosides and polyethylene glycol (PEG) on the same liposomes suppresses anti-PEG IgM production in mice. In addition, we recently observed that pDNA incorporated in PEGylated cationic liposomes (PCLs) induces anti-DNA IgM, which could be a hurdle to the development of efficient gene delivery systems. Therefore, the focus of this study was to determine if the copresentation of gangliosides and DNA on the same PCL would suppress antibody production against DNA. PCLs including DNA induced both anti-PEG IgM production and anti-DNA IgM production. The extent of anti-PEG and anti-DNA IgM production was likely dependent on the immunogenicity of the complexed DNA. Treatment of clodronate-containing liposomes, which causes a depletion of phagocytic cells, suppressed anti-PEG IgM production from PCLs that did not include DNA but failed to suppress anti-PEG IgM production from PCLs that complexed DNA (PCLD). Both anti-PEG IgM and anti-DNA IgM was induced in T-cell-deficient nude mice as well as in normal mice following treatment with PCLs and PCLD, respectively. These results indicate that phagocytic cells contribute to anti-PEG IgM production but not to anti-DNA IgM production, while T-cells do not contribute to any form of antibody production. The copresentation of gangliosides and DNA significantly reduced anti-PEG IgM production but unfortunately did not reduce anti-DNA IgM production. It appears that the immunosuppressive effect of gangliosides, presumably via the CD22 signaling pathway, is limited only to anti-PEG immunity.

en: Molecular Pharmaceutics

ja: Molecular Pharmaceutics