Dose-Dependent Production of Anti-PEG IgM after Intramuscular PEGylated-Hydrogenated Soy Phosphatidylcholine Liposomes, but Not Lipid Nanoparticle Formulations of DNA, Correlates with the Plasma Clearance of PEGylated Liposomal Doxorubicin in Rats

PEGylated lipid nanoparticle-based Covid-19 vaccines,includingPfizer's BNT162b2 and Moderna's mRNA-1273, have beenshown to stimulate variable anti-PEG antibody production in humans.Anti-PEG antibodies have the potential to accelerate the plasma clearanceof PEGylated therapeutics, such as PEGylated liposomes and proteins,and compromise their therapeutic efficacy. However, it is not yetclear whether antibody titers produced by PEGylated Covid-19 vaccinessignificantly affect the clearance of PEGylated therapeutics. Thisstudy examined how anti-PEG IgM levels affect the pharmacokineticsof PEGylated liposomal doxorubicin (PLD) and compared the immunogenicityof a lipid nanoparticle formulation of linear DNA (DNA-LNP) to standardPEG-HSPC liposomes. DNA-LNP was prepared using the same compositionand approach as Pfizer's BNT162b2, except linear double-strandedDNA was used as the genetic material. PEGylated HSPC-based liposomeswere formulated using the lipid rehydration and extrusion method.Nanoparticles were dosed IM to rats at 0.005-0.5 mg lipid/kgbody weight 1 week before evaluating the plasma pharmacokinetics ofclinically relevant doses of PLD (1 mg/kg, IV) or PEGylated interferon alpha 2a (Pegasys, 5 mu g/kg, SC). Plasma PEG IgM was comparedbetween pre- and 1-week post-dose blood samples. The results showedthat anti-PEG IgM production increased with increasing PEG-HSPC liposomedose and that IgM significantly correlated with the plasma half-life,clearance, volume of distribution, and area under the curve of a subsequentdose of PLD. The plasma exposure of Pegasys was also significantlyreduced after initial delivery of 0.005 mg/ml PEG-HSPC liposome. However,a single 0.05 mg/kg IM dose of DNA-LNP did not significantly elevatePEG IgM and did not alter the IV pharmacokinetics of PLD. These datashowed that PEGylated Covid-19 vaccines are less immunogenic comparedto standard PEGylated HSPC liposomes and that there is an antibodythreshold for accelerating the clearance of PEGylated therapeutics.

Automated summary

PEGylated lipid nanoparticle-based Covid-19 vaccines can induce anti-PEG antibodies in humans, which may affect the efficacy of PEGylated therapeutics. This study found that anti-PEG IgM levels can influence the pharmacokinetics of PEGylated liposomal chemotherapy drugs and are dose-dependent. However, the DNA-LNP vaccine has a lesser impact on anti-PEG IgM production and does not alter the pharmacokinetics of chemotherapy drugs.