Chapter 11 - Peptide and Protein Bioconjugation: A Useful Tool to Improve the Biological Performance of Biotech Drugs

Abstract

This chapter discusses why bioconjugation of peptides and proteins is a useful tool to improve the biological performance of biotech drugs. The covalent conjugation of poly(ethylene glycol) (PEG) chains to proteins, known as PEGylation, has been successfully developed as a means of varying the in vivo properties of protein drugs. This technique offers less frequent administration to patients, greater convenience, and improved efficacy. PEG is a hydrophilic, biocompatible polymer approved by the main regulatory agencies, namely EMEA and FDA, for parenteral administration. The PEGylation of a protein can be achieved by random or selective conjugation protocols that yield the covalent attachment of one or more polymer chains to specific anchoring functions on the protein surface. Polymer conjugation induces size enlargement, charge and surface modifications, and protein shielding, which ultimately result in improved solubility, stability, enhanced immunological profile, prolonged permanence in the body and altered tissue localization, and cellular uptake. The beneficial effects of PEGylation usually compensate for the reduced biological activities of proteins modified by polymer conjugation. PEGylation has a strong effect on the pharmacokinetic profiles of proteins because it prolongs their presence in the bloodstream, increases their bioavailability, and modifies their biodistribution profiles. Renal clearance represents one of the main routes of protein elimination from the bloodstream. The glomerular capillary walls in the kidneys are organized into highly structured architectures with specialized barrier properties that control the ultrafiltration of hydrophilic macromolecules, namely proteins and polymers, and their reabsorption at the level of the proximal tubule. Both ultrafiltration and reabsorption depend on the composition, sizes, and charges of the circulating molecules.