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Drug delivery: Brushing off antigenicity

Nature Biomedical Engineering volume 1, Article number: 0019 (2017) Cite this article

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Conjugation of a diabetes drug with a brush polymer reduces the reactivity of the drug conjugate towards pre-existing polymer antibodies in human plasma and improves the drug's performance in diabetic mice.

Therapeutic peptides and proteins can make safe and effective drugs for humans. Over 100 such drugs have so far been approved for clinical use1,2, and interest in developing more is high given the increased rate of discovery of new biological targets and of new peptides and proteins with untapped therapeutic potential. However, naturally occurring peptides and proteins are often unstable, or have poor physicochemical properties or short half-lives in blood. These limitations lead to short efficacy time windows and frequent dosing, which reduce patient compliance and clinical appeal. Half-life extension techniques, such as drug depots or recombinant fusions with the Fc region of an antibody or of albumin, have however decreased the dosage of biologic drugs from twice daily to once a week or once a month3. One of the most established and commercially successful ways of synthetically extending a biologic's half-life is PEGylation — the covalent attachment of bioactive molecules to a poly(ethylene glycol) (PEG) chain. Since the early 1990s, over 10 PEGylated biological drugs have been approved by the US Food and Drug Administration (FDA), with many more currently enlisted in both early and late clinical trials3. Although PEG has been regarded as a non-immunogenic material with a proven safety record in humans, antibodies against it have recently been found in patients taking PEG–drug conjugates and in healthy individuals4. Reporting in Nature Biomedical Engineering, Ashutosh Chilkoti and colleagues now show that a brush-like, PEG-mimic polymer overcomes obstacles associated with current PEGylation techniques5. In particular, they demonstrate that a conjugate of exendin-4 (exendin) — a clinical drug for type 2 diabetes — and the PEG mimic has a markedly extended half-life, improved pharmacodynamics and, most notably, eliminates PEG antigenicity in human plasma without compromising biological efficacy in mouse models.

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Figure 1: A PEGylation approach for improving drug half-life and eliminating PEG antigenicity.

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Authors and Affiliations

  1. Kang Choon Lee is at the School of Pharmacy, Sungkyunkwan University, Suwon 16469, Korea.,

    Kang Choon Lee

  2. Seulki Lee is at The Russell H. Morgan Department of Radiology and Radiological Sciences and The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.,

    Seulki Lee

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  1. Kang Choon Lee
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  2. Seulki Lee
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Correspondence to Kang Choon Lee or Seulki Lee.

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Lee, K., Lee, S. Drug delivery: Brushing off antigenicity. Nat Biomed Eng 1, 0019 (2017). https://doi.org/10.1038/s41551-016-0019

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  • DOI: https://doi.org/10.1038/s41551-016-0019

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