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Enhancement of the specific activities of PEGylated proteins by a simple procedure using a reversible amino-protective reagent

Research Project

Project/Area Number 13672385
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
Research InstitutionOsaka University

Principal Investigator

TSUTSUMI Yasuo  Osaka University, Graduate School of Pharmaceutical Sciences, Research Associate, 薬学研究科, 助手 (50263306)

Co-Investigator(Kenkyū-buntansha) NAKAGAWA Shinsaku  Osaka University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (70207728)
TADANORI Mayumi  Osaka University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (00098485)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsPEGylation / interleukin-6 / cytokine / Drug Delivery System / ポリエチレングリコール / プロテオーム創薬 / ドラッグデリバリーシステム / 創薬 / トランスレーショナルリサーチ / ライフサイエンス / 医療
Research Abstract

We developed a novel method for the chemical modification of proteins with synthetic polymers to increase the therapeutic efficacy of the former in vivo. A pH-reversible amino-protective reagent, dimethylmaleic anhydride (DMMAn), was used for modification of interleukin-6 (IL-6) with polyethylene glycol (PEG). The novel PEGylated IL-6 (DmPEG-IL-6), which had been pretreated with DMMAn before PEGylation, showed up to a 140% increase in in vitro specific activity compared with PEG-IL-6 that had been synthesized by the previous method. Moreover, DmPEG-IL-6 caused thrombopoiesis more potently in mice than PEG-IL-6. The DmPEG-IL-6, having 3-4 PEG chains attached to the cytokine, showed the strongest thrombopoietic effect among the DmPEG-IL-6s with different molecular sizes that were tested. PEG-IL-6 had a 500-fold higher potency in stimulating thrombopoiesis than native IL-6, and DmPEG-IL-6 Fr.1 achieved a threefold higher thrombopoietic effect than PEG-IL-6. In addition, side-effects, such as an increase in the plasma fibrinogen level, were not observed after injection of either PEG-IL-6s or DmPEG-IL-6s. Additionally, we also found that PEGylation of tumor necrosis factor-alpha and G-CSF using DMMAn increased their specific activities. These results suggest that PEGylation with DMMAn pretreatment may become a useful means for clinical cytokine delivery.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (13 results)

All Other

All Publications (13 results)

  • [Publications] Kamada H., et al.: "Synthesis of poly(vinylpyrrolidone-co-dimethyl maleic anhydride) co-polymer and its application as a renal targeting carrier"Nature Biotechnology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto Y., et al.: "Creation of lysine-deficient TNF-alpha with full bloactivity using phage libraries produces a novel PEGylation system"Nature Biotechnology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto Y., et al.: "Molecular design of bioconjugated cell adhesion peptide with a water-soluble polymeric modifier for enhancement of antimetastatic effect"Current Drug Target. 3・2. 123-130 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsunoda S. et al.: "Selective enhancement of thrombopoietic activity of PEGylated interleukin 6 by a simple procedure using a reversible amino-protective reagent"Br. J. Haematol.. 112. 181-188 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsunoda S. et al.: "Selective enhancement of thrombopoietic activity of PEGylated interleukin 6 by a simple procedure using a reversible amino-protective reagent"Br. J. Haematol.. 112. 181-188 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto Y. et al.: "Molecular design of bioconjugated cell adhesion peptide with a water-soluble polymeric modifier for enhancement of antimetastatic effect"Current Drug Targets. 3(2). 123-130 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kamada H. et al.: "Synthesis of poly(vinylpyrrolldone-co-dimethyl maleic anhydride) co-polymer and its application as a renal targeting carrier"Nat. Biotechnol.. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto Y. et al.: "Creation of lysine-deficient TNF-a with full bioactivity using phage libraries produces a novel PEGylation system"Nat. Biotechnol.. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kamada H., et al.: "Synthesis of poly(vinylpyrrolidone-co-dimethyl maleic anhydride) co-polymer and its application as a renal targeting carrier"Nature Biotechnology. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamamoto Y., et al.: "Creation of lysine-deficient TNF-alpha with full bioactivity using phage libraries produces a novel PEGylation system"Nature Biotechnology. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamamoto Y., et al.: "Molecular design of bioconjugated cell adhesion peptide with a water-soluble polymeric modifier for enhancement of antimetastatic effect"Current Drug Target. 3・2. 123-130 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsunoda S. et al.: "Selective enhancement of thrombopoietic activity of PEGylated interleukin 6 by a simple procedure using a reversible amino-protective reagent"Br. J. Haematol.. 112. 181-188 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamamoto Y et al.: "Molecular design of bioconjugated cell adhesion peptide with a water-soluble polymeric modifier for enhancement of antimetastatic effect"Current Drug Targets. (in press).

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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