Work

Enhancing the Pharmacokinetic Profile of Interleukin 2 through Site-Specific Conjugation to a Selective Small-Molecule Transthyretin Ligand

Year: 2021

Type: article

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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.1c01426

Authors: Fang Liu, Toufiq Ul Amin, Dengpan Liang, Miki S. Park, Mamoun M. Alhamadsheh

Institution: University of the Pacific

Language: English

Topic: Monoclonal and Polyclonal Antibodies Research

Subfield: Radiology, Nuclear Medicine and Imaging

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Institute of General Medical Sciences