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Is the Use of Polyethylene Glycol a Catch-22?

Polyethylene glycol (PEG) is a synthetic ethylene oxide polymer with a repetitive structure of (O-CH2-CH2)n. In the 1970s Dr. Frank Davis reported the modification of a new recombinant protein with PEG with the goal of enhanced pharmacokinetics. The process of covalent coupling of PEG to other molecules including proteins, peptides, antibodies, and aptamers became known as PEGylation. In March 1990 Adagen became the first PEGylated protein to be approved by the FDA.1 Since then a large number of PEGylated products have been brought to market as PEGylation results in improved stability, increased solubility, and extended in vivo half life. Most recently a PEGylated lipid was used as an excipient in both the Moderna and Pfizer-BioNTech COVID19 vaccines with the Messenger RNA (mRNA) encased in a bubble of PEGylated lipids.2 Generally, PEG has been considered non-toxic; however, in the past decades there has been growing evidence that individuals have developed anti-PEG antibodies (APAs).

Incidence of anti-PEG antibodies among the general population

PEG is also commonly found in a variety of commercial products such as personal hygiene products, cleaning products, pharmaceutical additives and some processed foods. As a result, people are frequently exposed to PEG and there is an incidence of anti-PEG antibodies among the general population regardless of exposure to PEGylated pharmaceuticals suggesting environmental exposure. Although reports of severe allergic reactions to PEG are exceedingly rare, it is important to understand the clinical impact of anti-PEG antibodies. In a clinical trial for PEG-asparaginase, rapid clearance of PEG-asparaginase closely correlated with APAs.3 In the case of Pegloticase it was found that 42% of patients developed APAs that were associated with rapid drug clearance, loss of efficacy and infusion reactions following treatment.4

As PEGylation continues to be an effective method for drug delivery, it is inevitable that patients may be treated with numerous PEGylated therapeutics and APA responses induced by one PEGylated drug could change the efficacy of subsequent PEGylated therapies. Thus, there is a need to screen for APAs prior to beginning clinical trials and monitor the development of APAs during trials as well as the need to dose PEGylated therapies accordingly. And now with a significantly large population being exposed to PEGylated lipids in the mRNA vaccines, there are concerns about adverse events (allergic reactions and/or rapid clearance) in people that have APAs. Currently, there doesn’t seem to be significant risk with only a small number of allergic reactions being reported and positive vaccine results being reported.5

REFERENCES:

1. Rodman, M. J. (1990). Drug News. RN, 53(8), 101.
2. https://www.future-science.com/doi/full/10.4155/tde-2016-0006
3. Armstrong, J.K., Hempel, G., Koling, S., Chan, L.S., Fisher, T., Meiselman, H.J., Garratty, G., 2007. Cancer 110, 103–111.
4. Krystexxa (pegloticase) prescribing information, 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125293s085lbl.pdf Reference ID:3929005 and Hershfield, M.S., Ganson, N.J., Kelly, S.J., Scarlett, E.L., Jaggers, D.A., Sundy, J.S., 2014. Arthritis Res.Ther. 16, R63.
5. https://www.sciencemag.org/news/2020/12/suspicions-grow-nanoparticles-pfizer-s-covid-19-vaccine-trigger-rare-allergic-reactions

Image credit: https://www.sciencedirect.com/science/article/abs/pii/S0168365916304175

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