Peptide and protein PEGylation III: advances in chemistry and clinical applications

The practice of covalent coupling of poly(ethylene glycol) to pharmaceutical proteins, commonly named PEGylation, is now regarded as an extremely useful procedure to overcome certain problems faced in the development and use of protein drugs. The continuing interest in PEGylation is well documented by the number of papers and patents that have appeared since the discovery of this methodology by Davis and Abuchowski in the late 1970s [1]. Indeed, PEGylation has become the dominant protein drug delivery system for the biotech industry, with sales of PEGylated protein drugs reaching over $4 billion [2]. The practical importance of the procedure is clearly demonstrated by the number of protein-PEG conjugates reaching the market or making it to an advanced state of clinical experimentation. Examples of commercial products using PEGylation are Adagen®, Oncaspar®, PEGIntron®, PEGASYS®, Neulasta® and Somavert®, and a dozen other PEG-proteins which are now in advanced clinical trials [3]. Although this methodology must be considered a mature technique, new developments arising from research and applications justify a new ADDR issue on this subject, following the two previous ones appearing in this Journal in 2002 and 2003 (volumes 54(4) and 55(10)). Originating as a novelty, in recent years there has been a shift from academic to industrial interest in PEGylation technology. This may be understood, considering that this research is close to market interests and, therefore, the technology is now accepted as a standard technique in industrial settings. The present third issue on PEGylation takes into account the results of both fundamental and applied research, with the latter addressing the practical problems of protein drug formulation, as well as the clinical evaluation of new PEGylated products. The first chapter, by Brocchini and Shaunak (Imperial College of London, U.K.), addresses the important problem of obtaining site-specific protein PEGylation to avoid the loss of biological activity, an inconvenience often observed in cytokine or enzyme conjugation. The proposed method is based on an original and intriguing chemistry that involves only the exposed protein disulphide bonds as sites of modification [4]. The second chapter, by Fontana and Veronese research groups (University of Padua, Italy), illustrates the structural and dynamic