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Polyethylene glycol (PEG)-associated immunological effects triggered by clinically relevant lipid nanoparticles (preprint)
biorxiv; 2022.
Preprint
in English
| bioRxiv | ID: ppzbmed-10.1101.2022.11.24.516986
ABSTRACT
Polyethylene glycol (PEG)-conjugated lipid has significantly contributed to the success of three approved lipid nanoparticles (LNP)-delivered therapeutics, particularly two COVID-19 mRNA vaccines. It is known that some PEG derivatives could elicit anti-PEG antibodies and subsequently form “antigen-antibody” complexes with newly injected PEGylated agents, leading to pharmacokinetic changes, reduced therapeutic efficacy and even hypersensitivity reactions. With the large-scale vaccination of mRNA vaccines, it has become an imminent task to elucidate the possible PEG-associated immunological effects induced by clinically relevant LNP. Up to date there are only four related studies, all of which are clinical observations emphasizing on the changes of PEG-specific antibodies upon injection of mRNA vaccines. Unfortunately, contradictory and inconclusive data were obtained due to significant person-to-person and study-to-study variabilities. To clarify the PEG-associated immunological effects of clinically relevant LNP in a model system with least “noise”, we initiated an animal study using the PEGylated LNP of BNT162b2 (with the largest number of recipients) as a representative LNP and simulated the clinical practice. Through designing a series of time points and three doses correlated with the PEG amount contained in three approved LNP-based drugs, we demonstrated that generation and changes of anti-PEG IgM and IgG were time- and dose-dependent. Unexpectedly, our data revealed that unlike other PEG derivatives belonging to thymus-independent antigens (TI-Ag), PEGylated LNP not only induced isotype switch and production of anti-PEG IgG, but caused immune memory, leading to rapid enhancement and longer lasting time of both anti-PEG IgM and IgG upon repeated injection. Importantly, pharmacokinetic studies discovered that initial injection of PEGylated LNP accelerated the blood clearance of subsequently injected LNP. These findings will refresh our understandings on PEGylated LNP and possible other PEG derivatives, and may lead to optimization of both premarket guidelines and clinical protocols of PEGylated LNP-delivered therapeutics.
Full text:
Available
Collection:
Preprints
Database:
bioRxiv
Language:
English
Year:
2022
Document Type:
Preprint
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