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A novel anti-integrin monoclonal antibody that attenuates mouse liver fibrosis: Mechanism of action and therapeutic application

Research Project

Project/Area Number 26293174
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionHiroshima University

Principal Investigator

Yokosaki Yasuyuki  広島大学, 保健管理センター, 准教授 (80210607)

Co-Investigator(Kenkyū-buntansha) 茶山 一彰  広島大学, 医歯薬保健学研究院(医), 教授 (00211376)
正木 崇生  広島大学, 大学病院, 教授 (30397913)
仙谷 和弘  広島大学, 医歯薬保健学研究院(医), 講師 (30508164)
Research Collaborator TSUJINO KAZUYUKI  カリフォルニア大学, サンフランシスコ校・肺バイオロジーセンター, 博士研究員
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000)
Fiscal Year 2016: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2015: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Keywordsfibrosis / antibody drug / integrin / myofibroblast / stellate cell / インテグリン / 肝線維症 / ノックアウトマウス / 抗体医薬 / TGF-β / 肺線維症 / 線維化 / インテグリンα8β1 / α-smooth muscle actin / 肝硬変 / 腎線維症 / 筋線維芽細胞 / 阻害抗体 / 腎硬化症
Outline of Final Research Achievements

The first integrin α8β1 blocking mAb (Patent 2011-537260) we have generated showed drastic effects on mouse hepatic fibrosis (Grant-in-aid for challenging exploratory research). We have analyzed α8β1 and demonstrated its weak TGF-β activation, expression on activated stellate cells, and induction of myofibroblastic differentiation. In the present study, to develop the mAb into a medical drug, we investigated anti-fibrotic effects on pulmonary and kidney fibrosis of the mAb, α8 expression on human fibrotic livers, anti-fibrotic effect in fibroblast specific α8 KO mice and epitope mapping of the mAb, which confirmed a potency of the mAb as a medical drug.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (29 results)

All 2017 2016 2015 2014 Other

All Int'l Joint Research (3 results) Journal Article (9 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 8 results,  Open Access: 8 results,  Acknowledgement Compliant: 2 results) Presentation (14 results) (of which Int'l Joint Research: 6 results) Book (1 results) Remarks (2 results)

  • [Int'l Joint Research] UCSF(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Medical University of South Carolina(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] UCSF, Lung Biology Center/University of South Carolina/University of Pennsylvania(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αv integrin interaction.2016

    • Author(s)
      Soltani AK, McCarthy DA, McKleroy W, Azary S, Sakuma S, Ha A, Tharp K, Yokosaki Y, Hart D, Stahl A, Atabai K.
    • Journal Title

      eLife

      Volume: 5

    • DOI

      10.7554/elife.13063

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ultra-superovulation for the CRISPR-Cas9-mediated production of gene-knockout, single- amino-acid-substituted, and floxed mice2016

    • Author(s)
      Yoshiko Nakagawa, Tetsushi Sakuma, Norihisa Nishimichi, Yasuyuki Yokosaki, Noriyuki Yanaka, Toru Takeo, Naomi Nakagata and Takashi Yamamoto
    • Journal Title

      Biology Open

      Volume: 5 Issue: 8 Pages: 1142-1148

    • DOI

      10.1242/bio.019349

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fibronectin extra domain A promotes liver sinusoid repair following hepatectomy2016

    • Author(s)
      Bridget Sackey-Aboagye, Abby L Olsen, Sarmistha M Mukherjee, Alexander Ventriglia, Yasayuki Yokosaki, Linda E Greenbaum, Gi Yun Lee, Hani Naga, Rebecca G Wells.
    • Journal Title

      PLoS one

      Volume: 11 Issue: 10 Pages: e0163737-e0163737

    • DOI

      10.1371/journal.pone.0163737

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] OPN-a induces muscle inflammation by increasing recruitment and activation of pro-inflammatory macrophages.2016

    • Author(s)
      Gina M Many, Yasuyuki Yokosaki, Kitipong Uaesoontrachoon, Peter P Nghiem, Luca Bello, Sherry Dadgar, Ying Yin, Jesse M Damsker, Heather B Cohen, Joe N Kornegay, David M Mosser, Kanneboyina Nagaraju, Eric Hoffman
    • Journal Title

      Experimental Physiology

      Volume: 101 Issue: 10 Pages: 1285-1300

    • DOI

      10.1113/ep085768

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αv integrin interaction.2016

    • Author(s)
      Sugiyama A, Kanno K, Nishimichi N, Yokosaki Y, Izuhara K, Ono J, Tazuma S.
    • Journal Title

      J Gastroenteroln

      Volume: in press Issue: 12 Pages: 1161-1174

    • DOI

      10.1007/s00535-016-1206-0

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation via αv integrin interaction.2016

    • Author(s)
      Sugiyama A, Kanno K, Nishimichi N, Yokosaki Y, Izuhara K, Ono J, Tazuma S.
    • Journal Title

      J Gastroenterol

      Volume: 印刷中

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Role of Integrin-α8 in Bleomycin-Induced Lung Injury2015

    • Author(s)
      Chi F. Hung, Nick M. Mark, Yu-Hua Chow, Norihisa Nishimichi, Yasuyuki Yokosaki, Lynn M. Schnapp
    • Journal Title

      Annals of the American Thoracic Society

      Volume: 12 Issue: Supplement 1 Pages: S74-S74

    • DOI

      10.1513/annalsats.201406-256mg

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Epitopes in α8β1 and other RGD-binding integrins delineate classes of integrin-blocking antibodies and major binding loops in α subunits2015

    • Author(s)
      Norihisa Nishimichi, Nagako Kawashima, Yasuyuki Yokosaki
    • Journal Title

      Scientific Reports

      Volume: 5 Issue: 1 Pages: 13756-13767

    • DOI

      10.1038/srep13756

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] インテグリンを介した線維化調節機構2015

    • Author(s)
      西道教尚、川島永子、横崎恭之
    • Journal Title

      細胞

      Volume: 47 Pages: 180-183

    • Related Report
      2014 Annual Research Report
  • [Presentation] Integrin α8β1 promotes tissue fibrosis via differentiation of myofibroblast -A potent therapeutic target on fibrosis-2017

    • Author(s)
      Nishimichi N, Kanno K, Sentani K, Sugiyama A, Ito M, Otani M, Hanaoka M, Yasui W, Yokosaki Y
    • Organizer
      Gordon research conference
    • Place of Presentation
      Ventura. CA, USA
    • Year and Date
      2017-01-29
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of conformational epitopes for integrin blocking mAbs against α3 and α5 subunits.2017

    • Author(s)
      Otani M, Nishimichi N, Ito M, Hanaoka M, Yoshizumi M, Yokosaki Y
    • Organizer
      Gordon research conference
    • Place of Presentation
      Ventura. CA, USA
    • Year and Date
      2017-01-29
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] インテグリン機能阻害モノクローナル抗体はインテグリンのリガンド結合ドメイン内特定領域を認識する2016

    • Author(s)
      西道 教尚、伊藤 益美、大谷 水景、花岡 みずほ、原山 郁花、横崎 恭之
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] ホモロジーモデリングによる立体構造を参照とするインテグリン機能阻害抗体のエピトープ同定2016

    • Author(s)
      大谷 水景、西道 教尚、伊藤 益美、花岡 みずほ、吉栖 正生、横崎 恭之
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] α-シヌクレインはインテグリンα9β1のリガンドである2016

    • Author(s)
      ○伊藤 益美、西道 教尚、大谷 水景、花岡 みずほ、横崎 恭之
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] Transglutaminase induced Polymeric α-synuclein binds to integrin α9β12016

    • Author(s)
      Yokosaki Y, Nishimichi N, Ito M
    • Organizer
      Gordon research conference
    • Place of Presentation
      Girona, Spain
    • Year and Date
      2016-07-10
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Anti-Fibrotic Monoclonal Antibodies against Integrin α8β1 Explained Long Term Lacking of the mAb2016

    • Author(s)
      Norihisa Nishimichi, Nagako Kawashima, Yasuyuki Yokosaki.
    • Organizer
      American Thoracic Society
    • Place of Presentation
      San Francisco, CA, USA
    • Year and Date
      2016-05-14
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Epitopes of Anti-Fibrotic Monoclonal Antibodies against Integrin 81 Explained Long Term Lacking of the mAb2016

    • Author(s)
      Norihisa Nishimichi, Nagako Kawashima, Yasuyuki Yokosaki.
    • Organizer
      American Thoracic Society
    • Place of Presentation
      San Francisco, CA, USA
    • Year and Date
      2016-05-14
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Periostin stimulates hepatic stellate cells via interaction with integrins: Novel functional roles for periostin in hepatic fibrosis2015

    • Author(s)
      Akiko Sugiyama, Keishi Kanno, Norihisa Nishimichi, Yasuyuki Yokosaki, Susumu Tazuma.
    • Organizer
      American Association for the Study of Liver Disease,
    • Place of Presentation
      Boston, MA, USA
    • Year and Date
      2015-11-07
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] インテグリンα8β1モノクローナル抗体の認識部位の同定2014

    • Author(s)
      西道教尚、横崎恭之
    • Organizer
      日本分子生物学会
    • Place of Presentation
      横浜
    • Year and Date
      2014-11-25 – 2014-11-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Periostin stimulate hepatic stellate cells via interaction with integrins: Novel functional roles for pristine in hepatic fibrosis2014

    • Author(s)
      Sugiyama A, Kanno K, Nishimichi N, Yokosaki Y, Tazuma S
    • Organizer
      American Association for the Study of Liver Disease
    • Place of Presentation
      ボストン、アメリカ合衆国
    • Year and Date
      2014-11-07 – 2014-11-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] Inhibition of pulmonary fibrosis by integrin α8β1 blocking antibody and TGF-β independent myofibroblast differentiation by α8β1 mediated signal2014

    • Author(s)
      Yokosaki Y, Nishimichi N, Kanno K, Sentani K
    • Organizer
      American Thoracic Society
    • Place of Presentation
      サンディエゴ、アメリカ合衆国
    • Year and Date
      2014-05-16 – 2014-05-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] α8β1 integrin and traction are necessary for activation of TGF-β in fibrosis2014

    • Author(s)
      Mark NM, Hung C, Chow H, Kennewick K, Lewis S, Nishimichi N, Yokosaki Y, Hinz B, Schnapp LM
    • Organizer
      American Thoracic Society
    • Place of Presentation
      サンディエゴ、アメリカ合衆国
    • Year and Date
      2014-05-16 – 2014-05-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] 新しい繊維化抑制薬シーズインテグリンα8β1抗体2014

    • Author(s)
      横崎恭之、西道教尚、仙谷和宏、菅野啓司、安井弥
    • Organizer
      日本呼吸器学会
    • Place of Presentation
      大阪
    • Year and Date
      2014-04-25 – 2014-04-27
    • Related Report
      2014 Annual Research Report
  • [Book] Transglutaminases2016

    • Author(s)
      Yasuyuki Yokosaki
    • Total Pages
      391
    • Publisher
      Springer
    • Related Report
      2015 Annual Research Report
  • [Remarks] インテグリン治療開発フロンティア研究室

    • URL

      http://home.hiroshima-u.ac.jp/integrin/Home.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] インテグリン治療開発フロンティア研究室

    • URL

      http://home.hiroshima-u.ac.jp/integrin/home.html

    • Related Report
      2014 Annual Research Report

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Published: 2014-04-04   Modified: 2022-02-16  

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