A method for extending the duration of the therapeutic effect of a type 2 diabetes drug in mice and that, crucially, eliminates a common adverse effect to drugs associated with pre-existing antibodies in patients, is described in a paper published online this week in the new journal Nature Biomedical Engineering.
Modifying a drug with an inert, biocompatible polymer such as poly(ethylene glycol) - a flexible chain-like molecule, also known as PEG - can reduce the drug’s interaction with the immune system. However, chronic exposure to PEG, which is present in commonly used consumer products, leads the immune system to generate antibodies against it, reducing the clinical efficacy of PEG-modified drugs and increasing the risk of adverse reactions to them.
Ashutosh Chilkoti and colleagues show that appending a polymer bearing short segments of ethylene glycol (and thus resembling a flexible, rod-shaped molecular brush) to a drug (exendin-4) used to treat type 2 diabetes eliminates the reactivity of the modified drug towards patient-derived antibodies against PEG. They also show that the polymer-modified drug increases the drug’s circulation time in blood, with a single injection maintaining normal blood glucose levels in mice for up to five days (120 hours), compared with only 6 hours for the drug alone. The authors suggest that their drug-modification strategy constitutes a next-generation technology for improving the safety and efficacy of therapeutics.