Next-Generation Drugs Circumvent Adverse Immune Response

By Gerald M. Slutzky, PhD
Posted on 13 Dec 2016

Drugs conjugated with a modified type of polyethylene glycol (PEG)-based polymer demonstrate enhanced and longer life performance without triggering an immune response from indigenous anti-PEG antibodies.

The delivery of peptide and protein drugs is often complicated by short half-lives and the consequent need for frequent injections that limit efficacy, reduce patient compliance, and increase treatment cost.

Image: An artist’s rendering that depicts troublesome antibodies (purple Ys) attacking conventional PEGylated drugs while ignoring the modified version (Photo courtesy of Stacey Qi, Duke University).

PEG polymers have been attached to drugs to slow the body's clearing of them from the bloodstream, greatly lengthening the duration of their effects. However, the pervasiveness of PEG in daily human life has caused many people to develop antibodies to the polymer that result in adverse allergic responses to PEGylated drugs.

Investigators at Duke University (Durham, NC, USA) have addressed this problem by conjugating drugs to a modified form of PEG: poly[oligo(ethylene glycol) methyl ether methacrylate] or POEGMA. They reported in the November 28, 2016, online edition of the journal Nature Biomedical Engineering 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 II diabetes mellitus - and POEGMA with precisely controlled molecular weights lowered blood glucose for up to 120 hours in fed mice.

The investigators also showed that an exendin-C-POEGMA conjugate with an average of nine side-chain ethylene glycol (EG) repeats exhibited significantly lower reactivity towards patient-derived anti-poly(ethylene glycol) (anti-PEG) antibodies than two [US] Food and Drug Administration-approved PEGylated drugs, and that reducing the side-chain length to three EG repeats completely eliminated PEG antigenicity without compromising in vivo efficacy.

"We started down a path to make PEG-like conjugates of protein drugs more efficiently and stumbled into the PEG antigenicity problem," said senior author Dr. Ashutosh Chilkoti, professor of biomedical engineering at Duke University. "This work has been an interesting journey with the unexpected twists and turns that makes research so rewarding."

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