Overcoming the PEG dilemma with Poly(2-ethyl-2-oxazoline) lipids in lipid nanoparticle formulations

• Global roll out of the mRNA vaccines revealed an unusual high rate of anaphylaxis. • Anti-PEG antibodies are boosted in individuals following vaccination and booster shots. • Anti-PEG antibodies can lead to accelerated clearance of PEGylated therapeutics. • Strategies to address “the PEG dilemma” are needed. • We have identified a PEOZ-lipid LNP formulation that fails to elicit an antibody response in a vaccine protocol in the rat. The introduction of PEG as a platform for drug delivery has revolutionized therapeutics across a myriad of drug classes – proteins, aptamers, small molecules, liposomes and more recently lipid nanoparticles. In the “pre-COVID-19 era” the incidence of adverse events to PEGylated therapeutics, and in particular serious adverse events, were rare. In the “post-COVID-19 era” where a majority of patients show boosted anti-PEG antibodies following vaccination the occurrence of adverse events is more common. This was heralded by an unusually high incidence rate of anaphylaxis during the global role out of the mRNA vaccines. The data suggest the major cause of anaphylaxis is pre-existing anti-PEG antibodies that are likely the result of PEG as an excipient in common household items from cosmetics to deodorant. Vaccination with the mRNA vaccines has been shown to boost anti-PEG IgM and IgG antibodies, with the Moderna vaccination in particular. We believe it is particularly important to address “the PEG dilemma” now as LNP technology enters mainstream medicine as an approach to address gene therapy, cancer vaccines, protein replacement and ultimately much more common disorders such as hypertension and diabetes.