Enhancing the Pharmacokinetic Profile of Interleukin 2 through Site-Specific Conjugation to a Selective Small-Molecule Transthyretin Ligand.
J Med Chem
; 64(19): 14876-14886, 2021 10 14.
Article
em En
| MEDLINE
| ID: mdl-34542267
ABSTRACT
Protein drugs hold great promise as therapeutics for a wide range of diseases. Unfortunately, one of the greatest challenges to be addressed during clinical development of protein therapeutics is their short circulation half-life. Several protein conjugation strategies have been developed for half-life extension. However, these strategies have limitations and there remains room for improvement. Here, we report a novel nature-inspired strategy for enhancing the in vivo half-life of proteins. Our strategy involves conjugating proteins to a hydrophilic small molecule that binds reversibly to the plasma protein, transthyretin. We show here that our strategy is effective in enhancing the pharmacokinetic and pharmacodynamic properties of human interleukin 2 in rats, potentially opening the door for more effective and safer cancer immunotherapies. To our knowledge, this is the first example of successful use of a small-molecule that not only extends the half-life but also maintains the smaller size, binding potency, and hydrophilicity of proteins.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pré-Albumina
/
Interleucina-2
/
Bibliotecas de Moléculas Pequenas
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article