rPEGylation of Uricase for Reduced Immunogenicity
L. Grieser,1 J. Schmidt,1 P. Dreier1 and H. Frey*1
1 Department of Chemistry, Johannes Gutenberg University Mainz, D-55128 Mainz, Germany
* hfrey@uni-mainz.de, phdreier@uni-mainz.de
PEGylation, the covalent attachment of poly(ethylene glycol) (PEG) to active substances, can improve the pharmacological profile of therapeutics.1 But besides the advantages of PEGylation, the presence and the emerging prevalence of anti-PEG antibodies is a great challenge, especially for repeatedly administered treatments for chronic diseases. 40% of patients show induction of anti-PEG antibodies after the treatment with PEGylated uricase (Krystexxa®), which is approved by the U.S. Food and Drug Administration for chronical gout.2 Furthermore, 50% of patients with high titers of anti-PEG antibodies prior to treatment show infusion reactions to the drug, of which 26% were categorized as severe and 6.5% as life threatening anaphylaxis.3
To overcome the challenge of anti-PEG antibodies, alternatives for PEG are investigated. We propose randomized PEG (rPEG), a structural isomer of PEG, which is synthesized by statistical anionic ring-opening polymerization of ethylene oxide and glycidyl methyl ether. rPEG shows, depending on the glycidyl methyl ether content, reduced anti-PEG antibody recognition.4
Based on these results, rPEGylated uricase seems promising to exhibit reduced immunogenic properties in comparison to the PEGylated analogue Krystexxa®. We demonstrate that rPEG218 can be activated via p-nitrophenylchloroformate and unselectively conjugated to uricase analogously to PEG and are further investigating the immunogenic properties of the conjugate.
References:
[1] Alconcel, S. N. S.; Baas, A. S.; Maynard, H. D. Polym. Chem. 2011, 2 (7), 1442.
[2] Lipsky, P. E.; Calabrese, L. H.; Kavanaugh, A.; Sundy, J. S.; Wright, D.; Wolfson, M.; Becker, M. A. Arthritis research & therapy 2014, 16 (2), R60.
[3] Ozer, I.; Kelly, G.; Gu, R.; Li, X.; Zakharov, N.; Sirohi, P.; Nair, S. K.; Collier, J. H.; Hershfield, M. S.; Hucknall, A. M.; Chilkoti, A. Advanced science 2022, 9 (11), e2103672.
[4] Dreier et al. 2025 (in press).