PEGylation of Biopharmaceuticals: A Review of Chemistry and Nonclinical Safety Information of Approved Drugs

Abstract

Modification of biopharmaceutical molecules by covalent conjugation of polyethylene glycol (PEG) molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules and has been used successfully in 12 approved drugs. Both linear and branched-chain PEG reagents with molecular sizes of up to 40 kDa have been used with a variety of different PEG derivatives with different linker chemistries. This review describes the properties of PEG itself, the history and evolution of PEGylation chemistry, and provides examples of PEGylated drugs with an established medical history. A trend toward the use of complex PEG architectures and larger PEG polymers, but with very pure and well-characterized PEG reagents is described. Nonclinical toxicology findings related to PEG in approved PEGylated biopharmaceuticals are summarized. The effect attributed to the PEG part of the molecules as observed in 5 of the 12 marketed products was cellular vacuolation seen microscopically mainly in phagocytic cells which is likely related to their biological function to absorb and remove particles and macromolecules from blood and tissues. Experience with marketed PEGylated products indicates that adverse effects in toxicology studies are usually related to the active part of the drug but not to the PEG moiety.

The polypeptide biophysics of proline/alanine‐rich sequences (PAS): Recombinant biopolymers with PEG‐like properties

“…Poly‐ethylene glycol (PEG) is an uncharged chemical polymer with broad application in biotechnology, biophysics, nanotechnology and biomedical research, not only as a common precipitant for proteins1 and nucleic acids2 but also for hydrophilic coating of particles or surfaces, preparation of hydrogels3 and, in particular, for conjugation to biopharmaceuticals 4, 5. Prominent features of PEG are its strong hydrophilicity, its disordered conformation in a dissolved state, which causes an expanded hydrodynamic volume as well as “crowding effect,” the availability in a variety of average sizes and its largely inert chemical and biological behavior 6…”

“…During the past two decades, PEG has seen increasing use in the development of therapeutic proteins and peptides with the goal to extend their intrinsically short circulation in blood or to reduce immunogenicity 4. When covalently conjugated to a pharmaceutically active compound, long PEG chains—typically 20–40 kDa—with their expanded radius of gyration slow down renal filtration through the glomerular pores and, thus, can extend plasma half‐life by up to one order of magnitude 7.…”

Targeting KCa1.1 Channels with a Scorpion Venom Peptide for the Therapy of Rat Models of Rheumatoid Arthritis

“…The final version may differ from this version. the length of efficacy of therapeutics by reducing renal clearance and decreasing the rate of proteolytic degradation (Harris and Chess, 2003;Turecek et al, 2016). Creating a PEGylated IbTX analog could therefore be used to increase its length of efficacy.…”

Targeting prostate cancer cells with genetically engineered polypeptide-based micelles displaying gastrin-releasing peptide

“…However, a significant background signal was observed with 1.5x ELP-C/ELP-K-Atto micelles which most likely was due to nonspecific binding. Different strategies can be applied to achieve reduced non-specific binding for future micelle designs, including covalent linkage of polyethylene glycol (PEG) to ELPs (Mishra et al, 2015;Turecek et al, 2016). Such measures will potentially lead to improved stability for in vivo studies.…”