Editors' ChoicePROTEIN DRUGS

A new lease on half-life

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Science Translational Medicine  14 Dec 2016:
Vol. 8, Issue 369, pp. 369ec201
DOI: 10.1126/scitranslmed.aal3699

Proteins are an important and growing class of therapeutics, but their clinical use is hampered by a “here today, gone today” problem—rapid clearance from the bloodstream. This short half-life often necessitates frequent injections that reduce patient compliance and increase costs. A common delivery strategy to overcome this issue is the conjugation of a shielding polymer such as polyethylene glycol (PEG) to the surface of the protein drug. Polymer conjugation elongates serum half-life, improves stability and solubility, and reduces the body’s immune response to the protein. However, the carrier also can spur an unwanted immune response. Now, Qi and colleagues describe a protein-polymer conjugation strategy that substantially increases protein serum half-life without promoting an antigenic response.

In some patients, the production of anti-PEG antibodies to PEGylated drugs compromises continued treatment. Furthermore, some individuals never treated with PEGylated drugs harbor anti-PEG antibodies in their bloodstream, likely in response to the many PEG-containing consumer products used today. The authors developed their new protein-polymer conjugate by growing a single chain of a PEG-like brush polymer, called POEGMA, from the C terminus of the peptide exenatide—a 4.1-kDa drug that improves insulin production in type 2 diabetes patients and exhibits a half-life in mice of only about 2 hours. In contrast, the administration of a 55-kDa exenatide-POEGMA conjugate significantly improved the pharmacokinetic profile, facilitating a reduction in blood glucose levels for 120 hours in mice (compared with 6 hours for the unmodified exenatide).

It was hypothesized that because the PEG side chains on the POEGMA were very short (≤ 9 units), they would not react with anti-PEG antibodies. Upon incubation with serum from patients with anti-PEG antibodies, exenatide-POEGMA conjugates with 9-unit PEG side chains exhibited reduced antibody binding compared with two positive controls, PEGylated drugs. Through the creation of alternative exenatide-POEGMA conjugates with much shorter (3-unit) PEG side chains, antigenicity was completely eliminated without compromising extended therapeutic effect in a fed mouse model. Prior to translation, future work is needed to assess immunogenicity—that is, the ability of conjugates to generate new antibody responses—in addition to antigenicity in a living system.

Y. Qi et al., A brush-polymer/exendin-4 conjugate reduces blood glucose levels for up to five days and eliminates poly(ethylene glycol) antigenicity. Nat. Biomed. Eng. 10.1038/s41551-016-0002 (2016). [Abstract]

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