Abstract
The covalent attachment of polyethylene glycol (PEG) to therapeutical proteins is an important route to develop biobetters for biomedical, biotech and pharmaceutical industries. PEG conjugation can shield antigenic epitopes of the protein, reduce degradation by proteolytic enzymes, enhance long-term stability and maintain or even improve pharmacokinetic and pharmacodynamics characteristics of the protein drug. Nonetheless, correct information in terms of the PEGylation process from reaction to downstream processing is of paramount importance for the industrial application and processing scale-up. In this review we present and discuss the main steps in protein PEGylation, namely: PEGylation reaction, separation of the products and final characterization of structure and activity of the resulting species. These steps are not trivial tasks, reason why bioprocessing operations based on PEGylated proteins relies on the use of analytical tools according to the specific pharmaceutical conjugate that is being developed. Therefore, the appropriate selection of the technical and analytical methods may ensure success in implementing a feasible industrial process.
Highlights
Therapies based on biological drugs represented a revolutionary innovation in the pharmaceutical industry due to the success to overcome medical challenges, such as haemophilia, diabetes, arthritis and diseases of the immune system
Another concern related to commercial protein drugs is of economic nature and is called “Patent Cliff”, a market phenomenon well described for chemical drugs that is happening with biological ones (Calo-Fernández, Martínez-Hurtado, 2012)
Proteins of different degrees of PEGylation may be separated by ion exchange chromatography (IEX) since for each polyethylene glycol (PEG) molecule attached to an amino group, for example, a PEGylated protein has one less positive charge and this chromatographic technique separates proteins based on net surface charge (Fee, Van Alstine, 2011)
Summary
Therapies based on biological drugs represented a revolutionary innovation in the pharmaceutical industry due to the success to overcome medical challenges, such as haemophilia, diabetes, arthritis and diseases of the immune system. The PEGylation strategy provides a number of advantages for protein conjugates, such as (i) protection of antigenic sites present on the protein surface, i.e. antigenic epitopes; (ii) prevention of in vivo degradation by endocytosis and proteolytic enzymes; (iii) increase in apparent protein size and hydrodynamic volume, which reduces renal filtration, alters biodistribution and increases in vivo half-life; (iv) increased water solubility and reduction of protein aggregates due to steric repulsion between the PEGylated surfaces; (v) increased thermal and long-term stability (Beck, Sanglier-Cianférani, Van Dorsselaer, 2012; Sassi, Nagarkar, Hamblin, 2015) It may promote sustained release of originator drug (Monfardini et al, 1995; Veronese, Caliceti, Schiavon, 1997). We review the main concepts, strategies and pitfalls of protein PEGylation aiming at biobetter manufacturing
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