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Tight-junction binderによる革新的血液脳関門制御技術の開発

Research Project

Project/Area Number 17J03990
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section国内
Research Field Medical pharmacy
Research InstitutionNagoya University

Principal Investigator

橋本 洋佑  名古屋大学, 環境医学研究所, 特別研究員(PD)

Project Period (FY) 2017-04-26 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsClaudiin-5 / Blood-brain barrier / Antibody / Tight junction / 血液脳関門 / 抗体 / Claudin-5
Outline of Annual Research Achievements

血液脳関門の回避・突破技術は、薬による効率的な中枢神経系疾患の治療法の開発のためには必要不可欠と言える。本研究は、血液脳関門の要である血管内皮細胞間が有するtight junctionの主要構成要素であるclaudin-5を標的とし、このclaudin-5の機能を阻害する抗体により細胞間隙を開口させる手法が、革新的な脳内への薬物送達技術に成り得るかを検証することを目的としている。
前年度までにバリア制御活性の強さに基づいて選抜した抗claudin-5抗体は、ヒトやサルのclaudin-5に結合するものの、マウスやラットといった実験動物のclaudin-5には結合性を示さないことを確認している。まず、in vivoでの活性確認を行うため、カニクイザルを用いたプレ実験を行うことにした。同一のカニクイザルに、週に1回、異なる濃度の抗claudin-5抗体を静脈内投与していき、抗体投与24時間後にフルオロセインナトリウム(分子量376.27)の静脈内投与を行った。この際、フルオロセインナトリウムの静脈内投与前、投与後10、30、60、120分に大槽から脳脊髄液の採取を行った。脳脊髄液中の蛍光量を測定していった結果、抗claudin-5抗体の投与により顕著に脳脊髄液中の蛍光量が最大で7倍程度増加していた。脳を構成する細胞においてclaudin-5を発現する細胞は血管内皮細胞のみであるため、この結果は抗claudin-5抗体がin vivoで血液脳関門の間隙を開口させたことを意味している。実験する個体数を増やすことが必要不可欠であるものの、抗claudin-5抗体の効果に期待が出来る結果であると言える。また、旧所属の共同研究者らが他施設でヒトclaudin-5をノックインしたマウスの作製に成功し、同マウスを用いた抗lcauidn-5抗体の効果を検証中である。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Report

(3 results)
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (15 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (10 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 9 results,  Open Access: 2 results) Presentation (2 results) (of which Int'l Joint Research: 2 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] Trinity College Dublin/Smurfit Institute of Genetics(アイルランド)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Tight junction modulation at the blood-brain barrier; Current and future perspectives.2020

    • Author(s)
      Hashimoto Yosuke, Campbell Matthew
    • Journal Title

      BBA-Biomembranes

      Volume: -

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Development of drug delivery system for treatment of central nervous system diseases targeting tight junctions2019

    • Author(s)
      Hashimoto Yosuke、Kondoh Masuo、Takeda Hiroyuki
    • Journal Title

      Drug Delivery System

      Volume: 34 Issue: 5 Pages: 374-384

    • DOI

      10.2745/dds.34.374

    • NAID

      130007801760

    • ISSN
      0913-5006, 1881-2732
    • Year and Date
      2019-11-25
    • Related Report
      2019 Annual Research Report
    • Open Access
  • [Journal Article] Potential for Tight Junction Protein?Directed Drug Development Using Claudin Binders and Angubindin-12019

    • Author(s)
      Hashimoto Yosuke、Tachibana Keisuke、Krug Susanne M.、Kunisawa Jun、Fromm Michael、Kondoh Masuo
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 16 Pages: 4016-4016

    • DOI

      10.3390/ijms20164016

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A Novel Platform for Cancer Vaccines: Antigen-Selective Delivery to Splenic Marginal Zone B Cells via Repeated Injections of PEGylated Liposomes2018

    • Author(s)
      Shimizu Taro、Abu Lila Amr S.、Kawaguchi Yoshino、Shimazaki Yuna、Watanabe Yuki、Mima Yu、Hashimoto Yosuke、Okuhira Keiichiro、Storm Gert、Ishima Yu、Ishida Tatsuhiro
    • Journal Title

      The Journal of Immunology

      Volume: 201 Issue: 10 Pages: 2969-2976

    • DOI

      10.4049/jimmunol.1701351

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anti-Claudin Antibodies as a Concept for Development of Claudin-Directed Drugs2018

    • Author(s)
      Hashimoto Yosuke、Okada Yoshiaki、Shirakura Keisuke、Tachibana Keisuke、Sawada Makoto、Yagi Kiyohito、Doi Takefumi、Kondoh Masuo
    • Journal Title

      Journal of Pharmacology and Experimental Therapeutics

      Volume: 368 Issue: 2 Pages: 179-186

    • DOI

      10.1124/jpet.118.252361

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Engineered membrane protein antigens successfully induce antibodies against extracellular regions of claudin-5.2018

    • Author(s)
      Hashimoto Y, et al.
    • Journal Title

      Sci Rep.

      Volume: 8 Issue: 1 Pages: 8383-8383

    • DOI

      10.1038/s41598-018-26560-9

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pancreatic adenocarcinoma upregulated factor has oncogenic functions in oral squamous cell carcinoma2018

    • Author(s)
      Sasahira T, Kurihara M, Nishiguchi Y, Nakashima C, Kirita T, Kuniyasu H.
    • Journal Title

      Histopathol

      Volume: 70 Pages: 539-548

    • DOI

      10.1016/j.ejps.2018.02.016

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Cell Assay for Detecting Anti-PEG Immune Response against PEG-Modified Therapeutics2018

    • Author(s)
      Shimizu Taro、Abu Lila Amr S.、Awata Mizuki、Kubo Yukiyo、Mima Yu、Hashimoto Yosuke、Ando Hidenori、Okuhira Keiichiro、Ishima Yu、Ishida Tatsuhiro
    • Journal Title

      Pharmaceutical Research

      Volume: 35 Issue: 11 Pages: 223-223

    • DOI

      10.1007/s11095-018-2505-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A hydroxyl PEG version of PEGylated liposomes and its impact on anti-PEG IgM induction and on the accelerated clearance of PEGylated liposomes2018

    • Author(s)
      Shimizu Taro、Abu Lila Amr S.、Fujita Risako、Awata Mizuki、Kawanishi Munehira、Hashimoto Yosuke、Okuhira Keiichiro、Ishima Yu、Ishida Tatsuhiro
    • Journal Title

      European Journal of Pharmaceutics and Biopharmaceutics

      Volume: 127 Pages: 142-149

    • DOI

      10.1016/j.ejpb.2018.02.019

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Claudin-5-Binders Enhance Permeation of Solutes across the Blood-Brain Barrier in a Mammalian Model2017

    • Author(s)
      Hashimoto Yosuke、Shirakura Keisuke、Okada Yoshiaki、Takeda Hiroyuki、Endo Kohki、Tamura Maki、Watari Akihiro、Sadamura Yoshifusa、Sawasaki Tatsuya、Doi Takefumi、Yagi Kiyohito、Kondoh Masuo
    • Journal Title

      J Pharmacol Exp Ther.

      Volume: 363 Issue: 2 Pages: 275-283

    • DOI

      10.1124/jpet.117.243014

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] Development of claudin-5 modulators and evaluation of their in vitro permeation-activity of soultes across the blood-brain barrier in a mammalian model2018

    • Author(s)
      Yosuke Hashimoto, Keisuke Shirakura, Yoshiaki Okada, Hiroyuki Takeda, Kohki Endo, Maki Tamura, Akihiro Watari, Yoshifusa Sadamura, Tatsuya Sawasaki, Keisuke Tachibana, Takefumi Doi, Kiyohito Yagi, Masuo Kondoh
    • Organizer
      2018 Controlled Release Society Annual Meeting & Exposition
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Safety evaluation of a human chimeric monoclonal antibody that recognizes the extracellular loop domain of claudin-22018

    • Author(s)
      Yosuke Hashimoto, Tomoyuki Hata, Minoru Tada, Manami Iida, Akihiro Watari, Yoshiaki Okada, Takefumi Doi, Hiroki Kuniyasu, Kiyohito Yagi, Masuo Kondoh
    • Organizer
      54ty Congress of the European Societies of Toxicology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 無細胞技術を活用し、血液脳関門バリア機能を担う クローディン5を阻害する抗体を創出

    • URL

      https://www.ehime-u.ac.jp/wp-content/uploads/2018/06/4522981e313ba7a68c88d42c4ac42e3c-1.pdf

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗CLDN-5抗体、及びその抗体を含有する医薬2017

    • Inventor(s)
      近藤昌夫、八木清仁、土井健史、岡田欣晃、橋本洋佑、他4名
    • Industrial Property Rights Holder
      近藤昌夫、八木清仁、土井健史、岡田欣晃、橋本洋佑、他4名
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report

URL: 

Published: 2017-05-25   Modified: 2024-03-26  

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