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      Zwitterionic gel encapsulation promotes protein stability, enhances pharmacokinetics, and reduces immunogenicity.

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          Abstract

          Advances in protein therapy are hindered by the poor stability, inadequate pharmacokinetic (PK) profiles, and immunogenicity of many therapeutic proteins. Polyethylene glycol conjugation (PEGylation) is the most successful strategy to date to overcome these shortcomings, and more than 10 PEGylated proteins have been brought to market. However, anti-PEG antibodies induced by treatment raise serious concerns about the future of PEGylated therapeutics. Here, we demonstrate a zwitterionic polymer network encapsulation technology that effectively enhances protein stability and PK while mitigating the immune response. Uricase modified with a comprehensive zwitterionic polycarboxybetaine (PCB) network exhibited exceptional stability and a greatly prolonged circulation half-life. More importantly, the PK behavior was unchanged, and neither anti-uricase nor anti-PCB antibodies were detected after three weekly injections in a rat model. This technology is applicable to a variety of proteins and unlocks the possibility of adopting highly immunogenic proteins for therapeutic or protective applications.

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          Author and article information

          Journal
          Proc. Natl. Acad. Sci. U.S.A.
          Proceedings of the National Academy of Sciences of the United States of America
          1091-6490
          0027-8424
          Sep 29 2015
          : 112
          : 39
          Affiliations
          [1 ] Department of Chemical Engineering, University of Washington, Seattle, WA 98195;
          [2 ] Department of Bioengineering, University of Washington, Seattle, WA 98195.
          [3 ] Department of Chemical Engineering, University of Washington, Seattle, WA 98195; Department of Bioengineering, University of Washington, Seattle, WA 98195 sjiang@uw.edu.
          Article
          1512465112
          10.1073/pnas.1512465112
          4593115
          26371311
          fa2cd7cc-e5f4-4d37-b316-b7420dc3554f
          History

          hydrogel,immune response,nanomedicine,protein delivery,zwitterionic polymer

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