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Study on therapeutic antibodies for Marburg virus disease

Research Project

Project/Area Number 21H02734
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49060:Virology-related
Research InstitutionHokkaido University

Principal Investigator

Takada Ayato  北海道大学, 人獣共通感染症国際共同研究所, 教授 (10292062)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2023: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2022: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2021: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Keywordsマールブルグウイルス / 細胞侵入 / 抗体 / エピトープ / 治療薬 / 抗体医薬 / ウイルス
Outline of Research at the Start

エボラ出血熱に対する治療薬として抗体医薬が承認されている。しかし、これまでに作製された治療用抗体はエボラウイルス1種のみに特異的であり、マールブルグウイルスには全く効果が無い。マールブルグウイルスはエボラウイルスと共にフィロウイルス科に属し、ヒトやサルに急性で致死率の高い感染症をひき起こす病原体であるにも関わらず、治療法開発は遅れている。そこで本研究では、これまでエボラウイルスに対する抗体医薬開発過程で得られた知見を基にして、マールブルグウイルスの感染性を効率よく中和する抗体を作出し、マールブルグ出血熱に対して有効な抗体医薬の開発を試みる。

Outline of Final Research Achievements

Mouse monoclonal antibodies with cross-neutralizing activity against multiple orthomarburgviruses (Marburg virus and Ravn virus) were generated. By identification of the amino acid substitutions of escape mutants for each antibody and detailed epitope analysis on the viral surface glycoprotein, these antibodies are predicted to inhibit membrane fusion between the cell membrane and the viral envelope or to inhibit binding with host cell receptors. We also determined the amino acid sequences of the variable regions of these neutralizing antibodies and succeeded in creating human-mouse chimeric antibodies. Furthermore, the therapeutic effects of administration of the produced antibodies were confirmed using a mouse model infected with Marburg virus.

Academic Significance and Societal Importance of the Research Achievements

オルソマールブルグウイルスは、ヒトに致死率の高いマールブルグ熱をひき起こす。近年のアフリカの流行国の拡大によって、予防・治療法開発が急務となった。同じウイルス科に属し同様の出血熱を引き起こすエボラウイルスに対しては2種類の抗体医薬がFDAに承認されているが、これらはマールブルグ熱には効果が無い。治療薬候補となっている幾つかの化合物に関してはヒトでの有効性が確認されておらず、さらに副作用が大きい。本研究では複数のオルソマールブルグウイルスを中和するモノクローナル抗体を作出するとともに、ヒト―マウスキメラ抗体の作出に成功した。これらの成果によって、マールブルグ熱治療薬の開発に資すると思われる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (33 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (5 results) Journal Article (17 results) (of which Int'l Joint Research: 12 results,  Peer Reviewed: 17 results,  Open Access: 11 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 6 results) Book (1 results)

  • [Int'l Joint Research] NIH/UTMB/La Jolla Institute for Immunology(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] ザンビア大学(ザンビア)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] NIH/UTMB(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] LABOVET/INRB(コンゴ民主共和国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] RML, NIH/UTMB(米国)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] ICTV Virus Taxonomy Profile: Filoviridae 20242024

    • Author(s)
      Biedenkopf Nadine、Bukreyev Alexander、Chandran Kartik、Di Paola Nicholas、Formenty Pierre B. H.、Griffiths Anthony、Hume Adam J.、Muhlberger Elke、Netesov Sergey V.、Palacios Gustavo、Paweska Janusz T.、Smither Sophie、Takada Ayato、Wahl Victoria、Kuhn Jens H.
    • Journal Title

      Journal of General Virology

      Volume: 105 Issue: 2

    • DOI

      10.1099/jgv.0.001955

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Development of an Immunochromatography Assay to Detect Marburg Virus and Ravn Virus2023

    • Author(s)
      Changula K, Kajihara M, Muramatsu S, Hiraoka K, Yamaguchi T, Yago Y, Kato D, Miyamoto H, Mori-Kajihara A, Shigeno A, Yoshida R, Henderson CW, Marzi A, Takada A
    • Journal Title

      Viruses

      Volume: 15 Issue: 12 Pages: 2349-2349

    • DOI

      10.3390/v15122349

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The evolution and determinants of neutralization of potent head-binding antibodies against Ebola virus2023

    • Author(s)
      Yu Xiaoying、Hastie Kathryn M.、Davis Carl W.、Avalos Ruben Diaz、Williams Dewight、Parekh Diptiben、Hui Sean、Mann Colin、Hariharan Chitra、Takada Ayato、Ahmed Rafi、Saphire Erica Ollmann
    • Journal Title

      Cell Reports

      Volume: 42 Issue: 11 Pages: 113366-113366

    • DOI

      10.1016/j.celrep.2023.113366

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Annual (2023) taxonomic update of RNA-directed RNA polymerase-encoding negative-sense RNA viruses (realm Riboviria: kingdom Orthornavirae: phylum Negarnaviricota)2023

    • Author(s)
      Kuhn J. H. et al.
    • Journal Title

      Journal of General Virology

      Volume: 104 Issue: 8 Pages: 1-55

    • DOI

      10.1099/jgv.0.001864

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Renaming of genera Ebolavirus and Marburgvirus to Orthoebolavirus and Orthomarburgvirus, respectively, and introduction of binomial species names within family Filoviridae2023

    • Author(s)
      Biedenkopf Nadine、Bukreyev Alexander、Chandran Kartik、Di Paola Nicholas、Formenty Pierre B. H.、Griffiths Anthony、Hume Adam J.、Muhlberger Elke、Netesov Sergey V.、Palacios Gustavo、Paweska Janusz T.、Smither Sophie、Takada Ayato、Wahl Victoria、Kuhn Jens H.
    • Journal Title

      Archives of Virology

      Volume: 168 Issue: 8 Pages: 220-220

    • DOI

      10.1007/s00705-023-05834-2

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Pathogenicity of Lloviu and Bombali Viruses in Type I Interferon Receptor Knockout Mice2023

    • Author(s)
      Fletcher Paige、Feldmann Friederike、Takada Ayato、Crossland Nicholas A、Hume Adam J、Albarino Cesar、Kemenesi Gabor、Feldmann Heinz、Muhlberger Elke、Marzi Andrea
    • Journal Title

      The Journal of Infectious Diseases

      Volume: 228 Issue: Supplement_7 Pages: S548-S553

    • DOI

      10.1093/infdis/jiad226

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] RNA Editing as a General Trait of Ebolaviruses2023

    • Author(s)
      Mehedi Masfique、Ricklefs Stacy、Takada Ayato、Sturdevant Dan、Porcella Stephen F、Marzi Andrea、Feldmann Heinz
    • Journal Title

      The Journal of Infectious Diseases

      Volume: 228 Issue: Supplement_7 Pages: S498-S507

    • DOI

      10.1093/infdis/jiad228

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Structural and Energetic Basis for Differential Binding of Ebola and Marburg Virus Glycoproteins to a Bat-Derived Niemann-Pick C1 Protein2023

    • Author(s)
      Igarashi Manabu、Hirokawa Takatsugu、Takada Ayato
    • Journal Title

      The Journal of Infectious Diseases

      Volume: 228 Issue: Supplement_7 Pages: S479-S487

    • DOI

      10.1093/infdis/jiad120

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 2022 taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales2022

    • Author(s)
      Kuhn J.H. et al.
    • Journal Title

      Archives of Virology

      Volume: 167 Issue: 12 Pages: 2857-2906

    • DOI

      10.1007/s00705-022-05546-z

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells2022

    • Author(s)
      Hattori T, Saito T, Miyamoto H, Kajihara M, Igarashi M, Takada A
    • Journal Title

      Viruses

      Volume: 14 Issue: 10 Pages: 2124-2124

    • DOI

      10.3390/v14102124

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Detection of anti-ebolavirus antibodies in Ghanaian pigs2022

    • Author(s)
      OGAWA Hirohito、OHYA Kenji、AYIZANGA Raphael、MIYAMOTO Hiroko、SHIGENO Asako、YAMADA Masao、TAKASHIMA Yasuhiro、INOUE-MURAYAMA Miho、TAKADA Ayato、BABOREKA KAYANG Boniface
    • Journal Title

      Journal of Veterinary Medical Science

      Volume: 84 Issue: 11 Pages: 1491-1494

    • DOI

      10.1292/jvms.22-0186

    • ISSN
      0916-7250, 1347-7439
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Multiple Routes of Antibody-Dependent Enhancement of SARS-CoV-2 Infection2022

    • Author(s)
      Okuya Kosuke、Hattori Takanari、Saito Takeshi、Takadate Yoshihiro、Sasaki Michihito、Furuyama Wakako、Marzi Andrea、Ohiro Yoichi、Konno Satoshi、Hattori Takeshi、Takada Ayato
    • Journal Title

      Microbiology Spectrum

      Volume: 10 Issue: 2

    • DOI

      10.1128/spectrum.01553-21

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mapping of Antibody Epitopes on the Crimean-Congo Hemorrhagic Fever Virus Nucleoprotein2022

    • Author(s)
      Lombe Boniface Pongombo、Saito Takeshi、Miyamoto Hiroko、Mori-Kajihara Akina、Kajihara Masahiro、Saijo Masayuki、Masumu Justin、Hattori Takanari、Igarashi Manabu、Takada Ayato
    • Journal Title

      Viruses

      Volume: 14 Issue: 3 Pages: 544-544

    • DOI

      10.3390/v14030544

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular Mechanisms Underlying the Cellular Entry and Host Range Restriction of Lujo Virus2022

    • Author(s)
      Saito Takeshi、Hattori Takanari、Okuya Kosuke、Manzoor Rashid、Miyamoto Hiroko、Kajihara Masahiro、Takada Ayato
    • Journal Title

      mBio

      Volume: 13 Issue: 1

    • DOI

      10.1128/mbio.03060-21

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional Importance of Hydrophobic Patches on the Ebola Virus VP35 IFN-Inhibitory Domain2021

    • Author(s)
      Kasajima N、Matsuno K、Miyamoto H、Kajihara M、Igarashi M、Takada A
    • Journal Title

      Viruses

      Volume: 13 Issue: 11 Pages: 2316-2316

    • DOI

      10.3390/v13112316

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural Insights into the Interaction of Filovirus Glycoproteins with the Endosomal Receptor Niemann-Pick C1: A Computational Study2021

    • Author(s)
      Igarashi Manabu、Hirokawa Takatsugu、Takadate Yoshihiro、Takada Ayato
    • Journal Title

      Viruses

      Volume: 13 Issue: 5 Pages: 913-913

    • DOI

      10.3390/v13050913

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales2021

    • Author(s)
      Kuhn JH.、Adkins S、Agwanda BR、Al Kubrusli R、Alkhovsky SV、Takada A 他245名
    • Journal Title

      Archives of Virology

      Volume: 166 Issue: 12 Pages: 3513-3566

    • DOI

      10.1007/s00705-021-05143-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] ウイルス性出血熱2023

    • Author(s)
      髙田礼人
    • Organizer
      第97回日本感染症学会総会・学術講演会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] フィロウイルス感染症2023

    • Author(s)
      髙田礼人
    • Organizer
      第166回日本獣医学会学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Niemann-Pick C1 heterogeneity controlling filovirus tropism to bat cells2023

    • Author(s)
      Ayato Takada
    • Organizer
      U.S.-Japan Cooperative Medical Sciences Program (USJCMSP) International Conference on Emerging Infectious Diseases (EID) in the Pacific Rim
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 抗体依存性感染増強2023

    • Author(s)
      髙田礼人
    • Organizer
      令和4 年度「感染・免疫・がん・炎症」全国共同研究拠点シンポジウム
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] フィロウイルス研究の最近の話題2022

    • Author(s)
      髙田礼人
    • Organizer
      第6回鹿児島大学感染症制御のためのシンポジウム
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Niemann-Pick C1 heterogeneity controlling filovirus tropism to bat cells2022

    • Author(s)
      Ayato Takada
    • Organizer
      10th International Filovirus Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Single nucleotide variants of human T-cell immunoglobulin mucin 1 affecting viral entry into cells2022

    • Author(s)
      Takanari Hattori, Takeshi Saito, Masahiro Kajihara, Manabu Igarashi, Ayato Takada
    • Organizer
      10th International Filovirus Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] T-cell immunoglobulin mucin 1の一塩基変異がウイルスの細胞侵入へ与える影響2022

    • Author(s)
      服部 貴成、斎藤 健、高館 佳弘、笠島 和、梶原 亜紀奈、宮本 洋子、梶原 将大、五十嵐 学、高田 礼人
    • Organizer
      第69回日本ウイルス学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Molecular mechanisms underlying the cellular entry and host range restriction of Lujo virus2021

    • Author(s)
      齋藤 健、奥谷 公亮、服部 貴成、梶原 将大、高田 礼人
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Inhibition of filovirus entry by cyclic peptides derived from the Niemann-Pick C1 loop structure2021

    • Author(s)
      髙橋 侑嗣、高舘 佳弘、宮本 洋子、梶原 将大、五十嵐 学、髙田 礼人
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Book] 創薬研究者がこれだけは知っておきたい最新のウイルス学2021

    • Author(s)
      髙田礼人他101名
    • Total Pages
      602
    • Publisher
      技術情報協会
    • ISBN
      9784861048555
    • Related Report
      2021 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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