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Application of anti-HMGB1 m Ab in intracerebral hemorrhage-induced brain injury in common marmoset and elucidation of HMGB1 translocation mechanism

Research Project

Project/Area Number 20K17930
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionOkayama University

Principal Investigator

WANG Dengli  岡山大学, 医歯薬学域, 助教 (40815693)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords抗体治療 / 脳出血 / HMGB1 / マーモセットモデル / コラゲナーゼ / 炎症
Outline of Research at the Start

脳出血は、有効な治療法がない重症疾病である。このため、脳出血は患者と介護者のQOLに大きな影響を与える。HMGB1は細胞核由来の活性物質であり、細胞外空間で炎症性サイトカイン様活性を示す。我々はこれまでに、ラット抗HMGB1 抗体の末梢投与がラット脳出血によって引き起こされる脳障害を顕著に改善することを示した。しかしながら、脳出血過程におけるHMGB1の核から細胞外へのトランスロケ ーション機構は、未だ明らかではない。本研究では、その過程を明らかにし、さらに、ヒト化 抗HMGB1抗体のマーモセット出血脳障害モデルにおける有効性を検証する。その結果は、前臨床POCレベルを上昇させると期待できる。

Outline of Final Research Achievements

Intracerebral hemorrhage (ICH) is a critical medical issue without effective treatment. High mobility group box-1 (HMGB1) acts as an inflammatory cytokine when released from cell nuclei. Prior research showed that anti-HMGB1 monoclonal antibody (mAb) significantly reduced brain damage in a rat ICH model, leading to the development of a humanized version (OKY001) for clinical use. This study tested the humanized mAb in marmosets, finding that it blocked HMGB1 release and reduced brain iron deposition, oxidative stress, and brain injury size 12 days post-ICH. It also hindered hemoglobin uptake by macrophages, delaying the clearance of hemoglobin and its toxic byproducts. Additionally, it mitigated weight loss and enhanced behavioral outcomes post-ICH, suggesting its potential as a new ICH treatment.

Academic Significance and Societal Importance of the Research Achievements

この研究は脳内出血(ICH)の治療法開発に新たな道を示し、HMGB1をターゲットとした治療が脳損傷を減少させる可能性を明らかにした。
効果的な治療法が患者の生活の質を向上させ、医療費の削減や社会復帰の促進に寄与することが期待される。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (16 results)

All 2024 2023 2022 2021 2020 Other

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (7 results) Remarks (1 results)

  • [Journal Article] Perineural Treatment with High Mobility Group Box-1 Monoclonal Antibody Prevents Initiation of Pain-Like Behaviors in Female Mice with Trigeminal Neuropathy2024

    • Author(s)
      Ma Simeng、Nakamura Yoki、Kochi Takahiro、Uemoto Suzuna、Hisaoka-Nakashima Kazue、Wang Dengli、Liu Keyue、Wake Hidenori、Nishibori Masahiro、Morioka Norimitsu
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 47 Issue: 1 Pages: 221-226

    • DOI

      10.1248/bpb.b23-00729

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2024-01-20
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protective effects of an anti-4-HNE monoclonal antibody against liver injury and lethality of endotoxemia in mice2023

    • Author(s)
      Qiao Handong、Morioka Yuta、Wang Dengli、Liu Keyue、Gao Shangze、Wake Hidenori、Ousaka Daiki、Teshigawara Kiyoshi、Mori Shuji、Nishibori Masahiro
    • Journal Title

      European Journal of Pharmacology

      Volume: 950 Pages: 175702-175702

    • DOI

      10.1016/j.ejphar.2023.175702

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Treatment of Marmoset Intracerebral Hemorrhage with Humanized Anti-HMGB1 mAb2022

    • Author(s)
      Dengli Wang, Daiki Ousaka, Handong Qiao, Ziyi Wang, Kun Zhao, Shangze Gao, Keyue Liu, Kiyoshi Teshigawara, Kenzo Takada, Masahiro Nishibori
    • Journal Title

      Cells

      Volume: 11 Issue: 19 Pages: 1-22

    • DOI

      10.3390/cells11192970

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Histamine induced high mobility group box-1 release from vascular endothelial cells through H1 receptor2022

    • Author(s)
      Shangze Gao, Keyue Liu, Wenhan Ku, Dengli Wang, Hidenori Wake, Handong Qiao, Kiyoshi Teshigawara, Masahiro Nishibori
    • Journal Title

      Front Immunol .

      Volume: 13 Pages: 1-15

    • DOI

      10.3389/fimmu.2022.930683

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] High-mobility group box 1-mediated hippocampal microglial activation induces cognitive impairment in mice with neuropathic pain2022

    • Author(s)
      Kazue Hisaoka-Nakashima, Kazuto Ohata, Natsuki Yoshimoto, Shintarou Tokuda, Nanako Yoshii, Yoki Nakamura, Dengli Wang, Keyue Liu, Hidenori Wake, Takayuki Yoshida, Yukio Ago, Kouichi Hashimoto, Masahiro Nishibori, Norimitsu Morioka
    • Journal Title

      Exp Neurol .

      Volume: 355 Pages: 114146-114146

    • DOI

      10.1016/j.expneurol.2022.114146

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] High Mobility Group Box-1 and Blood Brain Barrier Disruption2020

    • Author(s)
      Nishibori Masahiro、Wang Dengli、Ousaka Daiki、Wake Hidenori
    • Journal Title

      Cells

      Volume: 9 Issue: 12 Pages: 2650-2650

    • DOI

      10.3390/cells9122650

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Corticosterone Induces HMGB1 Release in Primary Cultured Rat Cortical Astrocytes: Involvement of Pannexin-1 and P2X7 Receptor-Dependent Mechanisms2020

    • Author(s)
      Hisaoka-Nakashima Kazue、Azuma Honami、Ishikawa Fumina、Nakamura Yoki、Wang Dengli、Liu Keyue、Wake Hidenori、Nishibori Masahiro、Nakata Yoshihiro、Morioka Norimitsu
    • Journal Title

      Cells

      Volume: 9 Issue: 5 Pages: 1068-1068

    • DOI

      10.3390/cells9051068

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Histidine-Rich Glycoprotein Inhibits High-Mobility Group Box-1-Mediated Pathways in Vascular Endothelial Cells through CLEC-1A2020

    • Author(s)
      Gao Shangze、Wake Hidenori、Sakaguchi Masakiyo、Wang Dengli、Takahashi Youhei、Teshigawara Kiyoshi、Zhong Hui、Mori Shuji、Liu Keyue、Takahashi Hideo、Nishibori Masahiro
    • Journal Title

      iScience

      Volume: 23 Issue: 6 Pages: 101180-101180

    • DOI

      10.1016/j.isci.2020.101180

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Treatment of intracerebral hemorrhage with humanized a-HMGB1 mAb in non-human primate brain2021

    • Author(s)
      王登莉
    • Organizer
      第139回日本薬理学会近畿部会
    • Related Report
      2021 Research-status Report
  • [Presentation] The therapeutic effects of humanized anti-HMGB1 mAb on intracerebral hemorrhage-induced brain injury in marmoset.2021

    • Author(s)
      王登莉
    • Organizer
      第44回日本神経科学学会
    • Related Report
      2021 Research-status Report
  • [Presentation] 抗HMGB1抗体による脳内出血の治療: 霊長類マーモセットを用いた検討2021

    • Author(s)
      王登莉
    • Organizer
      第36回創薬・薬理フォーラム(岡山)
    • Related Report
      2021 Research-status Report
  • [Presentation] Treatment of intracerebral hemorrhage with humanized a-HMGB1 mAb in non-human primate brain2021

    • Author(s)
      王登莉
    • Organizer
      第95回日本薬理学会年会
    • Related Report
      2021 Research-status Report
  • [Presentation] 脳出血時のミクログリアにおけるHMGB1トランスロケーションに関する検討2020

    • Author(s)
      小橋和馬、長谷川玲央、松川力嗣, 劉克約, 喬寒棟, 和氣秀徳,逢坂大樹,王登莉,西堀正洋
    • Organizer
      創薬・薬理フォーラム岡山
    • Related Report
      2020 Research-status Report
  • [Presentation] HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes2020

    • Author(s)
      Dengli Wang, Keyue Liu, Kiyoshi Teshigawara, Hidenori Wake, and Masahiro Nishibori
    • Organizer
      第137回日本薬理学会近畿部会
    • Related Report
      2020 Research-status Report
  • [Presentation] The therapeutic effects of anti-HMGB1 mAb on subdural hematoma-induced brain injury in rats2020

    • Author(s)
      Dengli Wang, Shangze Gao, Keyue Liu, Hidenori Wake,Kiyoshi Teshigawara, Shuji Mori and Masahiro Nishibori
    • Organizer
      第43回日本神経科学学会
    • Related Report
      2020 Research-status Report
  • [Remarks] Research Map (王 登莉)

    • URL

      https://researchmap.jp/okayaku2017

    • Related Report
      2022 Research-status Report

URL: 

Published: 2020-04-28   Modified: 2025-01-30  

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