Challenges for PEGylated Proteins and Alternative Half-Life Extension Technologies Based on Biodegradable Polymers

PEGylation, the chemical conjugation of polyethylene glycol (PEG) to proteins, peptides and small molecules, is currently widely used to extend the half-life of therapeutic molecules, with 10 products already in the market. Despite its proven success, PEGylation may not be suitable for some of the newer protein binders, such as antibody fragments and protein scaffolds, which need to be administered in large doses for chronic therapy as concentrated solutions for subcutaneous injection. This short review highlights the deficiencies of PEGylation, as well as the industrially pursued alternatives based on biodegradable polymers. Eventually, the competitiveness of the newer techologies will be proven in comparative preclinical and clinical studies covering aspects like pharmacokinetics, pharmacodynamics, toxicity and stability.