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

Journal Article (Journal Article)

The delivery of therapeutic peptides and proteins is often challenged by a short half-life, and thus the 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 - 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 9 side-chain ethylene glycol (EG) repeats exhibits significantly lower reactivity towards patient-derived anti-poly(ethylene glycol) (PEG) antibodies than two FDA-approved PEGylated drugs, and that reducing the side-chain length to 3 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.

Full Text

Duke Authors

Cited Authors

  • Qi, Y; Simakova, A; Ganson, NJ; Li, X; Luginbuhl, KM; Özer, I; Liu, W; Hershfield, MS; Matyjaszewski, K; Chilkoti, A

Published Date

  • 2016

Published In

Volume / Issue

  • 1 /

PubMed ID

  • 28989813

Pubmed Central ID

  • PMC5627778

International Standard Serial Number (ISSN)

  • 2157-846X

Digital Object Identifier (DOI)

  • 10.1038/s41551-016-0002


  • eng

Conference Location

  • England