Pegylated cytokines: potential application in immunotherapy of cancer.

Conjugation of the polymer polyethylene glycol (PEG) to proteins can significantly decrease their clearance from plasma, thus increasing their half-lives in vivo. The increased half-life of PEG-proteins is directly proportional to the total molecular weight of the construct. This approach has been used to design cytokine constructs that can be administered once a week, rather than on a daily or alternate-day schedule. Two cytokines for which this approach appears to be successful are PEG-interferon-alpha-2a (PEG-IFNalpha-2a) and PEG-granulocyte colony- stimulating factor (PEG-G-CSF). Both use high molecular weight PEG (20 to 40kD) to give sufficiently long duration in vivo. In the case of PEG-G-CSF conjugates, the in vivo efficacy is directly proportional to molecular weight, whereas the in vitro activity is inversely proportional, suggesting that overall duration of contact is more important than the affinity of the interaction. Conjugates of a number of other cytokines have been prepared, but until recently, few have used the high molecular weight polymers. In the future, as this approach is taken to make new PEG-cytokine constructs, thorough pharmacokinetic studies will be essential for their development and clinical use.