PEGylated Proteins: How Much Does Molecular Weight Matter?

Polyethylene glycols (PEGs) are inert polymers of repeating ethylene oxide subunits. Attaching PEGs to therapeutic proteins may reduce the protein's immunogenicity and antigenicity, improve solubility and stability, slow protein degradation, and increase the half-life (t_½). This usually results in less frequent administration, improved quality of life and convenience, and potentially better adherence and lower costs. The advantages and disadvantages of PEGylated proteins differ according to the structure of the PEG moiety, particularly its molecular weight. The larger the PEG molecular weight, the longer the t_½ and time to steady state. PEGs have low toxicity and undergo minimal metabolism. The PEG moiety usually undergoes renal elimination and is excreted in urine, but with greater molecular weights, renal elimination declines and biliary excretion increases. Because PEG molecules are not broken down, there is potential for PEGs to accumulate in the cytoplasm, forming vacuoles, mostly in macrophages, although this does not affect their function. The risk of vacuolation increases with molecular weights > 30 kDa. However, even high molecular weight PEGs are used at doses markedly lower than the European Medicines Agency safety threshold for paediatric use. People can develop antibodies to PEGs, and this may increase the overall clearance of the PEGylated protein if antibody levels are sufficiently high (> 500 ng/mL according to one modelling study). In conclusion, it is important for physicians to understand how PEG molecular weight and architecture can impact stability, immunogenicity, glomerular filtration and cellular uptake, to better understand the overall safety, efficacy and pharmacological profile of PEGylated proteins.