Linear Polyglycerol for N-terminal-selective Modification of Interleukin-4

Polymer conjugation to biologics is of key interest to the pharmaceutical industry for the development of potent and long acting biotherapeutics, with poly(ethylene glycol) (PEG) being the gold standard. Within the last years, unwanted PEG-related side effects (immunological reactions, antibody formation) arose, therefore creating several attempts to establish alternative polymers with similar potential to PEG. In this article, we synthesized N-terminal bioconjugates of the potential therapeutic human interleukin-4 (hIL-4 WT) with linear polyglycerol (LPG) of 10 and 40 kDa and compared it with its PEG analogs of same nominal weights. Polyglycerol is a highly hydrophilic polymer with good biocompatibility and therefore represents an alternative polymer to PEG. Both polymer types resulted in similar conjugation yields, comparable hydrodynamic sizes and an unaltered secondary structure of the protein after modification. LPG- and PEG-bioconjugates remained stable in human plasma, whereas binding to human serum albumin (HSA) decreased after polymer modification. Furthermore, only minor differences in bioactivity were observed between LPG- and PEG-bioconjugates of same nominal weights. The presented findings are promising for future pharmacokinetic evaluation of hIL-4-polymer bioconjugates. (C) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Automated summary

Polymer conjugation to biologics is crucial for the development of potent and long acting biotherapeutics. In this study, the potential of linear polyglycerol (LPG) as an alternative polymer to poly(ethylene glycol) (PEG) was investigated. The results showed that LPG and PEG bioconjugates exhibited similar conjugation yields, hydrodynamic sizes, and protein activity. These findings provide promising insights for future pharmacokinetic evaluation of LPG-bioconjugates of therapeutic proteins.