title: Optimized clinical performance of growth hormone with an expanded genetic code.
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.affiliation: Ambrx Incorporated, 10975 North Torrey Pines Road, La Jolla, CA 92037, USA. ho.cho@ambrx.com
authors.forename: Ho
authors.initials: H
authors.lastname: Cho
authors.forename: Tom
authors.initials: T
authors.lastname: Daniel
authors.forename: Ying Ji
authors.initials: YJ
authors.lastname: Buechler
authors.forename: David C
authors.initials: DC
authors.lastname: Litzinger
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Maio
authors.forename: Anna-Maria Hays
authors.initials: AM
authors.lastname: Putnam
authors.forename: Vadim S
authors.initials: VS
authors.lastname: Kraynov
authors.forename: Bee-Cheng
authors.initials: BC
authors.lastname: Sim
authors.forename: Stuart
authors.initials: S
authors.lastname: Bussell
authors.forename: Tsotne
authors.initials: T
authors.lastname: Javahishvili
authors.forename: Sami
authors.initials: S
authors.lastname: Kaphle
authors.forename: Guillermo
authors.initials: G
authors.lastname: Viramontes
authors.forename: Mike
authors.initials: M
authors.lastname: Ong
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chu
authors.forename: G C
authors.initials: GC
authors.lastname: Becky
authors.forename: Ricky
authors.initials: R
authors.lastname: Lieu
authors.forename: Nick
authors.initials: N
authors.lastname: Knudsen
authors.forename: Paola
authors.initials: P
authors.lastname: Castiglioni
authors.forename: Thea C
authors.initials: TC
authors.lastname: Norman
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Axelrod
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hoffman
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kimmel
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004704:Endocrinology / Q000379:methods; D014644:Genetic Variation; D019382:Human Growth Hormone / Q000235:genetics* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D015202:Protein Engineering / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012270:Ribosomes / Q000737:chemistry
chemical_list: C476995:3-(4-acetylphenyl)-2-aminopropanoic acid; D010455:Peptides; D011108:Polymers; D019382:Human Growth Hormone; D011092:Polyethylene Glycols; D010649:Phenylalanine