Optimized clinical performance of growth hormone with an expanded genetic code

Area of Science:

• Biotechnology
• Protein Engineering
• Pharmacology

Background:

• The ribosomal incorporation of nonnative amino acids into polypeptides offers a method to enhance therapeutic protein properties.
• Current protein therapeutics often face limitations in efficacy and dosing frequency.

Purpose of the Study:

• To conduct the first clinical study of a biosynthetic protein produced using an expanded genetic code.
• To evaluate the efficacy and safety of a modified human growth hormone (hGH) with enhanced pharmacological properties.

Main Methods:

• Incorporation of p-acetylphenylalanine (pAcF), a nonnative amino acid, into hGH at specific sites.
• Site-specific conjugation of polyethylene glycol (PEG) to create homogeneous hGH variants.
• Pharmacodynamic studies in GH-deficient rats and clinical trials in GH-deficient adults.

Main Results:

• A mono-PEGylated hGH mutant (modified at residue 35) exhibited favorable pharmacodynamic properties in preclinical models.
• Clinical studies demonstrated that the biosynthetic hGH was comparable in efficacy and safety to native hGH.
• The modified hGH showed increased potency and allowed for reduced injection frequency in patients.

Conclusions:

• The use of nonnative amino acids via an expanded genetic code is a viable strategy for optimizing protein therapeutics.
• Biosynthetic proteins can be engineered to possess superior pharmacological profiles compared to their native counterparts.
• This approach holds significant potential for improving treatment outcomes and patient compliance for protein-based therapies.