Editors' ChoiceTherapeutic Proteins

Longer-Lived Proteins

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Science Translational Medicine  13 Jan 2010:
Vol. 2, Issue 14, pp. 14ec7
DOI: 10.1126/scitranslmed.3000810

Proteins used as therapies for disease range from insulin for treating diabetes to interferon for treating cancer and hepatitis. In addition to hormones and cytokines, this class of drugs includes growth factors, blood factors, enzymes, and antibodies. Researchers continue to search for new and improved therapeutic proteins, making this area a rapidly growing pharmaceutical field. One of the challenges in the development of these drugs is that they are often rapidly cleared from the body, reducing functional drug half-life. Current methods to protect the drugs from degradation and clearance include the attachment of "blocking" molecules, such as polyethylene glycol. However, these methods can increase the manufacturing time and add undesirable side effects to the drug. In an alternative approach, Schellenberger et al. constructed a gene fusion to attach a large polypeptide chain with protective properties (XTEN) to a target therapeutic peptide—the diabetes drug exenatide—during protein synthesis by bacteria. This fusion molecule, E-XTEN, had minimal immunogenic effects and exhibited up to a ~125-fold increase in drug half-life as compared with the unmodified version. When given to mice 48 hours before a glucose challenge, E-XTEN displayed a therapeutic effect against this challenge, whereas the unmodified drug did not, having already been cleared from the mice. This research demonstrates a new method for extending the half-life of therapeutic proteins, potentially opening a door into research on proteins that may have been previously disregarded as therapeutics because of their brief half-lives as well as allowing for the development of decreased dosing of current peptide pharmaceuticals.

Schellenberger et al., A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner. Nat. Biotechnol. 27, 1186–1190 (2009). [Full Text]

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