Optimized clinical performance of growth hormone with an expanded genetic code.

Journal: Proceedings Of The National Academy Of Sciences Of The United States Of America
Published:
Abstract

The ribosomal incorporation of nonnative amino acids into polypeptides in living cells provides the opportunity to endow therapeutic proteins with unique pharmacological properties. We report here the first clinical study of a biosynthetic protein produced using an expanded genetic code. Incorporation of p-acetylphenylalanine (pAcF) at distinct locations in human growth hormone (hGH) allowed site-specific conjugation with polyethylene glycol (PEG) to produce homogeneous hGH variants. A mono-PEGylated mutant hGH modified at residue 35 demonstrated favorable pharmacodynamic properties in GH-deficient rats. Clinical studies in GH-deficient adults demonstrated efficacy and safety comparable to native human growth hormone therapy but with increased potency and reduced injection frequency. This example illustrates the utility of nonnative amino acids to optimize protein therapeutics in an analogous fashion to the use of medicinal chemistry to optimize conventional natural products, low molecular weight drugs, and peptides.

Authors
Ho Cho, Tom Daniel, Ying Buechler, David Litzinger, Zhenwei Maio, Anna-maria Putnam, Vadim Kraynov, Bee-cheng Sim, Stuart Bussell, Tsotne Javahishvili, Sami Kaphle, Guillermo Viramontes, Mike Ong, Stephanie Chu, G Becky, Ricky Lieu, Nick Knudsen, Paola Castiglioni, Thea Norman, Douglas Axelrod, Andrew Hoffman, Peter Schultz, Richard Dimarchi, Bruce Kimmel