PEGylated Proteins: Evaluation of Their Safety in the Absence of Definitive Metabolism Studies

Abstract

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...

Long-acting pegylated human GH in children with GH deficiency: a single-dose, dose-escalation trial investigating safety, tolerability, pharmacokinetics and pharmacodynamics

“…NNC126-0083 is a long-acting GH preparation that has previously been shown to possess a potential once-weekly PK and PD treatment profile after single and multiple administration to healthy adults (6, 7) and multiple administrations to adults with GHD (8). The preparation utilises the prolongation of the in vivo mean residence time resulting from pegylation, a strategy that has successfully been applied to several drugs approved for human use (12)(13)(14). This study examined the short-term safety, tolerability, PK and PD profiles of single s.c. doses of NC126-0083 administered to children with GHD.…”

PEGylated Biopharmaceuticals

“…PEG has a simple repetitive structure, is chemically inert, and has low toxicity (Webster, Didier et al 2007;Schellekens, Hennink, and Brinks 2013). Findings including adverse effects observed in nonclinical studies of approved PEGylated biopharmaceuticals are usually related to the intended pharmacological actions of the active drug and not to the PEG moiety (Webster, Didier et al 2007;Kang, Deluca, and Lee 2009;Jevsevar, Kunstelj, and Porekar 2010;Ivens et al 2013).…”

“…Findings including adverse effects observed in nonclinical studies of approved PEGylated biopharmaceuticals are usually related to the intended pharmacological actions of the active drug and not to the PEG moiety (Webster, Didier et al 2007;Kang, Deluca, and Lee 2009;Jevsevar, Kunstelj, and Porekar 2010;Ivens et al 2013). However, PEG-related histologic changes, characterized as cellular vacuolation in certain tissues and cell types, have been observed in nonclinical toxicology studies for approximately half of the approved PEGylated drugs (Tables 1 and 2).…”

PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma

“…It is anticipated that either PEG-PTX or the free PEG released following the hydrolysis of PEG-PTX would be partially cleared by mucociliary clearance and by alveolar macrophages. The fraction absorbed in the systemic circulation would likely be eliminated by renal clearance [30]. Considering the large PEG size and the high doses delivered, long-term safety studies are needed to ascertain the safety of inhaled PEG-PTX.…”