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Int J Hematol. 1998 Jul;68(1):1-18.

PEGylation of cytokines and other therapeutic proteins and peptides: the importance of biological optimisation of coupling techniques.

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Poly MASC Pharmaceuticals PLC, Hampstead, London, UK.


Polyethylene glycol (PEG) modification, PEGylation, is a well established technique which has the capacity to solve or ameliorate many of the problems of protein and peptide pharmaceuticals. It is one of the most important of the molecule altering structural chemistry (MASC) techniques and in many settings is enabling technology. The use of PEG as a linker molecule is also beginning to make a contribution to the production of exciting new products. We have previously reviewed the marked differences between methods of PEGylation and the surprising and dramatic impact of different coupling techniques (using different activated PEGs) on factors such as retention of bioactivity, stability and immunogenicity of the resulting PEGylated proteins and peptides. Numerous factors play a part in this variation: the presence or absence of linkers between the PEG and the target molecule; the nature and stability of the bond(s) between the PEG, linker and target; the impact of PEG attachment on surface charge; the coupling conditions; and the relative toxicity of the activated polymer and/or coproduct(s). These are not, however, the only sources of qualitative differences in PEGylated products. Our own experience whilst developing a linkerless PEGylation technique (i.e. one attaching only PEG to the target molecule), which we devised to overcome all the major problems of pre-existing PEGylation techniques, was that considerable modification of the prototype method and a process of 'biological optimisation' was required to achieve good results in terms of conservation of bioactivity. Biological optimisation has not, as far as we are aware, been systematically applied by other groups working in PEGylation. It is the term we use to describe an iterative process for examining and refining all the steps in the PEGylation process, including manufacturing the activated polymer, in order to achieve the best possible conservation of bioactivity and other beneficial features of the method. The application of this biologically optimised PEGylation technique, using tresyl monomethoxy PEG (TMPEG), to a variety of target proteins reveals, as outlined in this review, an exceptional ability to conserve biological activity of the target. This, and the benefit of adding nothing other than PEG itself (which has an excellent safety record), to the protein, as well as other manufacturing and practical advantages, makes the method ideal for the modification of cytokines and other therapeutic proteins.

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