A brush-polymer/exendin-4 conjugate reduces blood glucose levels for up to five days and eliminates poly(ethylene glycol) antigenicity

• Published in: Nature biomedical engineering Vol. 1; no. 1
• Main Authors: Qi, Yizhi, Simakova, Antonina, Ganson, Nancy J., Li, Xinghai, Luginbuhl, Kelli M., Ozer, Imran, Liu, Wenge, Hershfield, Michael S., Matyjaszewski, Krzysztof, Chilkoti, Ashutosh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2017; Nature Publishing Group
• Subjects: 631/61/2297; 631/61/2298; 631/61/54/152; 639/166/985; 639/638/455; Antibodies; Antigenicity; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Blood; Blood glucose; Conjugates; Conjugation; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Drugs; Glucose; Immunoglobulins; Injection; Peptides; Polyethylene glycol; Polymers
• ISSN: 2157-846X; 2157-846X
• DOI: 10.1038/s41551-016-0002

The delivery of therapeutic peptides and proteins is often challenged by short half-lives and the consequent need for frequent injections that limit efficacy, reduce patient compliance and increase treatment cost. Here, we demonstrate that a single subcutaneous injection of site-specific (C-terminal) conjugates of exendin-4 (exendin)—a therapeutic peptide that is clinically used to treat type 2 diabetes mellitus—and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) with precisely controlled molecular weights lowered blood glucose for up to 120 h in fed mice. Most notably, we show that an exendin-C-POEGMA conjugate with an average of nine side-chain ethylene glycol (EG) repeats exhibits significantly lower reactivity towards patient-derived anti-poly(ethylene glycol) (anti-PEG) antibodies than two US FDA-approved PEGylated drugs, and that reducing the side-chain length to three EG repeats completely eliminates PEG antigenicity without compro­mising in vivo efficacy. Our findings establish the site-specific conjugation of POEGMA as a next-generation PEGylation technology for improving the pharmacological performance of traditional PEGylated drugs, whose safety and efficacy are hindered by pre-existing anti-PEG antibodies in patients. Conjugation of exendin-4 — a drug to treat type 2 diabetes — with a poly(ethylene glycol) (PEG)-based brush polymer reduces the conjugate's reactivity towards anti-PEG antibodies and leads to lower blood glucose levels in mice for up to 5 days after a single injection.