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Abstract
None of the formulation adjustments prevented efficacy loss associated with elevated anti-PEG immunoglobulin responses.
- A single dose of lipid nanoparticles (LNPs) can trigger adaptive immune responses against polyethylene glycol (PEG), leading to neutralization of subsequent doses.
- Adjustments in PEG-lipid chemistry, PEG concentration, mRNA cargo, and administration route did not mitigate efficacy loss after initial anti-PEG antibody responses.
- Efficacy loss was consistently linked to increased levels of anti-PEG immunoglobulin M (IgM) and, in some cases, immunoglobulin G (IgG).
- Lowering PEG concentration reduced immunogenicity but also decreased potency of the LNPs.
- Intraperitoneal administration resulted in the strongest immune responses upon re-dosing with LNPs.
- Anti-PEG immune responses compromised the delivery efficacy of any PEGylated LNP formulation, including an FDA-approved version.
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mRNA Technology