Optimized clinical performance of growth hormone with an expanded genetic code

被引：162

作者：

Cho, Ho ^{[1
]}

Daniel, Tom ^{[2
]}

Buechler, Ying Ji ^{[1
]}

Litzinger, David C. ^{[3
]}

Maio, Zhenwei ^{[1
]}

Putnam, Anna-Maria Hays ^{[1
]}

Kraynov, Vadim S. ^{[1
]}

Sim, Bee-Cheng ^{[1
]}

Bussell, Stuart ^{[1
]}

Javahishvili, Tsotne ^{[1
]}

Kaphle, Sami ^{[1
]}

Viramontes, Guillermo ^{[1
]}

Ong, Mike ^{[1
]}

Chu, Stephanie ^{[1
]}

Becky, G. C. ^{[1
]}

Lieu, Ricky ^{[4
]}

Knudsen, Nick ^{[1
]}

Castiglioni, Paola ^{[2
]}

Norman, Thea C. ^{[1
]}

Axelrod, Douglas W. ^{[1
]}

Hoffman, Andrew R. ^{[5
]}

Schultz, Peter G. ^{[6
]}

DiMarchi, Richard D. ^{[7
]}

Kimmel, Bruce E. ^{[8
]}

机构：

[1] Ambrx Inc, La Jolla, CA 92037 USA

[2] Celgene Corp, Summit, NJ 07901 USA

[3] Amylin Pharmaceut Inc, Pharmaceut Sci, San Diego, CA 92121 USA

[4] Appl Mol Evolut, Prot Sci, San Diego, CA 92121 USA

[5] Stanford Univ, Dept Med, Stanford, CA 94305 USA

[6] Scripps Res Inst, La Jolla, CA 92037 USA

[7] Indiana Univ, Dept Chem, Bloomington, IN 47405 USA

[8] Howard Hughes Med Inst, Ashburn, VA 20147 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 22期

关键词：

protein engineering; endocrinology; bio-better; UNNATURAL AMINO-ACID; ESCHERICHIA-COLI; ADULT HEIGHT; PROTEINS; RECEPTOR; CHILDREN; EFFICACY; THERAPY; EPITOPE;

D O I：

10.1073/pnas.1100387108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：9060 / 9065

页数：6

共 24 条

[1] A General and Efficient Method for the Site-Specific Dual-Labeling of Proteins for Single Molecule Fluorescence Resonance Energy Transfer [J].