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

Publication ,  Journal Article
Qi, Y; Simakova, A; Ganson, NJ; Li, X; Luginbuhl, KM; Özer, I; Liu, W; Hershfield, MS; Matyjaszewski, K; Chilkoti, A
Published in: Nat Biomed Eng
2016

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.

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Published In

Nat Biomed Eng

DOI

ISSN

2157-846X

Publication Date

2016

Volume

1

Location

England

Related Subject Headings

  • 4003 Biomedical engineering
 

Citation

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Qi, Y., Simakova, A., Ganson, N. J., Li, X., Luginbuhl, K. M., Özer, I., … Chilkoti, A. (2016). A brush-polymer conjugate of exendin-4 reduces blood glucose for up to five days and eliminates poly(ethylene glycol) antigenicity. Nat Biomed Eng, 1. https://doi.org/10.1038/s41551-016-0002
Qi, Yizhi, Antonina Simakova, Nancy J. Ganson, Xinghai Li, Kelli M. Luginbuhl, Imran Özer, Wenge Liu, Michael S. Hershfield, Krzysztof Matyjaszewski, and Ashutosh Chilkoti. “A brush-polymer conjugate of exendin-4 reduces blood glucose for up to five days and eliminates poly(ethylene glycol) antigenicity.Nat Biomed Eng 1 (2016). https://doi.org/10.1038/s41551-016-0002.
Qi Y, Simakova A, Ganson NJ, Li X, Luginbuhl KM, Özer I, et al. A brush-polymer conjugate of exendin-4 reduces blood glucose for up to five days and eliminates poly(ethylene glycol) antigenicity. Nat Biomed Eng. 2016;1.
Qi, Yizhi, et al. “A brush-polymer conjugate of exendin-4 reduces blood glucose for up to five days and eliminates poly(ethylene glycol) antigenicity.Nat Biomed Eng, vol. 1, 2016. Pubmed, doi:10.1038/s41551-016-0002.
Qi Y, Simakova A, Ganson NJ, Li X, Luginbuhl KM, Özer I, Liu W, Hershfield MS, Matyjaszewski K, Chilkoti A. A brush-polymer conjugate of exendin-4 reduces blood glucose for up to five days and eliminates poly(ethylene glycol) antigenicity. Nat Biomed Eng. 2016;1.

Published In

Nat Biomed Eng

DOI

ISSN

2157-846X

Publication Date

2016

Volume

1

Location

England

Related Subject Headings

  • 4003 Biomedical engineering