Development of pegylated interferons for the treatment of chronic hepatitis C

The chemical attachment of poly(ethylene glycol) [PEG] to therapeutic prote ins produces several benefits, including enhanced plasma half-life, lower t oxicity, and increased drug stability and solubility. In certain instances, pegylation of a protein can increase its therapeutic efficacy by reducing the ability of the immune system to detect and mount an attack on the compo und. A PEG-protein conjugate is formed by first activating the PEG moiety so tha t it will react with, and couple to, the protein. PEG moieties vary conside rably in molecular weight and conformation, with the early moieties (monofu nctional PEGs; mPEGs) being linear with molecular weights of 12kD or less, and later moieties being of increased molecular weights. PEG2, a recent inn ovation in PEG technology, involves the coupling of a 30kD (or less) mPEG t o lysine that is further reacted to form a branched structure that behaves like a linear mPEG of much larger molecular weight. These compounds are pH and temperature stable, and this factor along with the large molecular weig ht may account for the restricted volume of distribution seen with drugs ut ilising these reagents. Three PEG-protein conjugates are currently approved for clinical use in the US, with more under clinical development. Pegademase is used in the treatm ent of severe combined immunodeficiency disease, pegaspargase for the treat ment of various leukaemias, and pegylated interferon-alpha for chronic hepa titis C virus infections. As illustrated in the case of the 2 pegylated int erferon-alphas, all pegylated proteins are not equal. The choice of PEG rea gent and coupling chemistry is critical to the properties of the PEG-protei n conjugate, with the molecular weight of the moiety affecting its rate and route of clearance from the body, and coupling chemistry affecting the str ength of the covalent attachment of PEG to therapeutic protein.