ABSTRACT:During the development of any PEGylated protein or peptide, toxicology in relevant species will be conducted prior to human exposure. Normally, comprehensive metabolism data accompany the toxicity studies for a small molecule. We have examined whether such studies would be relevant in the safety assessment of PEGylated material. Literature data indicate that the polyethylene glycol (PEG) associated with a biological molecule should provide no extra concern because the exposure-toxicity relationship of PEG in animals and humans has been thoroughly investigated and metabolism/excretion of PEG is well understood. Based on the comparisons of PEG exposure from PEGylated biological products and the exposure of PEG associated with toxicity in humans, the therapeutic index is large (approximately 600-fold or greater). Therefore, assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans.The conjugation of small proteins, peptides, and oligonucleotides with polyethylene glycol (PEG), or PEGylation, has become an increasingly common method of improving the half-life of biological products, mainly through reducing the urinary excretion of the molecule (Yang et al., 2004), but also by reducing the enzymic degradation due to the increased steric bulk (Veronese and Pasut, 2005). In addition, PEGylated biological products often exhibit a reduced affinity for the target receptor compared with the native precursor. This reduced affinity can lead to a lower clearance by target-mediated clearance mechanisms. Finally, the addition of the PEG moiety can have beneficial effects on the immunological profile of a molecule by reducing the ability of the compound to raise antibodies in humans (Mehvar, 2000).PEG is a polymer made up of identical ethylene glycol subunits. PEGs have a descriptor associated with them that represents the mean molecular weight of the molecule (i.e., PEG200 has a molecular weight of 200) (Smyth et al., 1955). The PEG molecules conjugated to proteins can also have the terminal hydroxyl group capped with a methyl group (Molineux, 2003). The structures of these PEGs are detailed in Fig. 1. Higher molecular weight PEGs can have some degree of branching. The PEGs used to conjugate biologicals are polydispersed in nature (i.e., have a range of molecular weights), and this can to lead to a range of drug molecules with potentially subtly different biological properties. The impact of polydispersity must be considered when dealing with these conjugated biological agents (Veronese and Pasut, 2005).To couple the PEG to the protein, peptide, or oligonucleotide, the PEG (generally monomethoxy PEG) is first activated. Several methods can be used to achieve this activation and coupling, including cyanuric chloride, 1,1Ј-carbonyldiimidazole, phenylchloroformate, or succi...

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