A brush-polymer/exendin-4 conjugate reduces blood glucose levels for up to five days and eliminates poly(ethylene glycol) antigenicity
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...
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Published in | Nature biomedical engineering Vol. 1; no. 1 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.01.2017
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 2157-846X 2157-846X |
DOI: | 10.1038/s41551-016-0002 |