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Optimized clinical performance of growth hormone with an expanded genetic code

  1. Bruce E. Kimmelh
  1. aAmbrx Incorporated, 10975 North Torrey Pines Road, La Jolla, CA 92037;
  2. bCelgene Corporation, 86 Morris Avenue, Summit, NJ 07901;
  3. cPharmaceutical Sciences, Amylin Pharmaceuticals Incorporated, 9360 Towne Centre Drive, San Diego, CA 92121;
  4. dProtein Sciences, Applied Molecular Evolution, 10300 Campus Point Drive, Suite 200, San Diego, CA 92121;
  5. eDepartment of Medicine, Endocrinology, Stanford University, Palo Alto, CA 94305;
  6. fThe Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92307;
  7. gDepartment of Chemistry, Indiana University, Bloomington, IN 47405; and
  8. hJanelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147

  1. Edited* by Christopher T. Walsh, Harvard Medical School, Boston, MA, and approved April 13, 2011 (received for review January 7, 2011)

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.

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: ho.cho{at}ambrx.com.

  • ↵2The contribution of A.R.H. to this publication was as a paid consultant and was not part of his Stanford University duties or responsibilities.

  • Author contributions: H.C., T.D., Y.J.B., D.C.L., Z.M., A.-M.H.P., B.-C.S., S.B., T.J., A.R.H., and R.D.D. designed research; Y.J.B., D.C.L., Z.M., A.-M.H.P., V.S.K., B.-C.S., S.B., T.J., S.K., G.V., M.O., S.C., B.G., R.L., N.K., and P.C. performed research; V.S.K., S.C., B.G., and P.G.S. contributed new reagents/analytic tools; H.C., T.D., Y.J.B., D.C.L., A.-M.H.P., B.-C.S., T.J., T.C.N., D.W.A., A.R.H., P.G.S., and R.D.D. analyzed data; and H.C., Y.J.B., D.C.L., A.-M.H.P., V.S.K., B.-C.S., S.B., T.C.N., A.R.H., P.G.S., R.D.D., and B.E.K. wrote the paper.

  • Conflict of interest statement: The authors declare a conflict of interest (such as defined by PNAS policy). This work was funded by Ambrx, Inc. (La Jolla, CA) and in part by Merck Serono (Geneva). As indicated in the author list, some of the authors are current or former employees of Ambrx, Celgene, Amylin Pharmaceuticals, or Applied Molecular Evolution. P.G.S. and R.D.D. are members of Ambrx’s board of directors and cofounders of the company and own company stock. A.R.H. is an advisor and consultant to Ambrx and Merck Serono and owns options for Ambrx. T.D., D.C.L., and B.E.K. are former employees of Ambrx and own stock in the company.

  • *This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1100387108/-/DCSupplemental.

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