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Identification of the most appropriate therapeutic target for PNH

Research Project

Project/Area Number 19K08862
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionOsaka University

Principal Investigator

Ueda Yasutaka  大阪大学, 医学系研究科, 助教 (30533848)

Co-Investigator(Kenkyū-buntansha) 西村 純一  大阪大学, 医学系研究科, 招へい教授 (80464246)
高森 弘之  大阪大学, 医学部附属病院, 医員 (80792077)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords発作性夜間ヘモグロビン尿症 / PNH / 溶血性貧血 / 抗補体薬 / 血管内溶血 / 血管外溶血 / プロペルジン / 補体 / 補体疾患
Outline of Research at the Start

発作性夜間ヘモグロビン尿症(PNH)は、補体の活性化を介した血管内溶血により貧血をきたす後天性疾患だが、抗補体薬であるエクリズマブは、補体終末経路の重要な分子であるC5を阻害し、溶血を阻止することで、貧血や関連症状を大きく改善した。しかし補体活性化経路の上流にあるC3の蓄積から、血管外溶血をきたす患者もおり、新たな抗補体薬が求められている。本研究では、試験管内で様々な補体阻害薬を用い、血管内・外溶血阻止の有効性を評価する一方、自然免疫である補体阻害による感染リスクの評価も行うことで、安全性の評価も行う。
上記実験を通じ、PNHの補体溶血治療に最適な標的を同定し、複雑な補体系の解明につなげる。

Outline of Final Research Achievements

Anti-C5 antibodies effectively blocks complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH), but some patients show poor response to the antibodies due to extravascular hemolysis manifested under anti-C5 treatment. Properdin is a component of the complement alternative pathway, and we found that anti-properdin antibody alone blocked hemolysis of PNH red blood cells, and hindered accumulation of C3 on the red blood cells in vitro, suggesting that the antibody blocks both intra- and extravascular hemolysis. The blood level of properdin was stably comparatively low in PNH patients. The antibody didn’t interfere with the classical and lectin pathways, suggesting it might mitigate the infectious risk in the patients under treatment. Those data suggest that blocking complement components consisting of the alternative pathway, especially properdin, may be one of the most appropriate therapeutic targets for PNH.

Academic Significance and Societal Importance of the Research Achievements

稀少疾患であるPNH患者に対して様々な新規治療薬が臨床開発中であるが、どの薬剤が患者にとって最適なのかはまだ分かっていない。今回の研究を通じて、PNHの新規治療薬の方向性として第2経路阻害が有望であることが明らかとなり、今後PNHの治療薬選択を考える上での重要な知見が得られた。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (15 results)

All 2022 2021 2020 2019

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 2 results) Presentation (9 results) (of which Int'l Joint Research: 9 results)

  • [Journal Article] Long-term follow-up of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: post-marketing surveillance in Japan2022

    • Author(s)
      Ikezoe Takayuki、Noji Hideyoshi、Ueda Yasutaka、Kanda Yoshinobu、Okamoto Shinichiro、Usuki Kensuke、Matsuda Takahisa、Akiyama Hirozumi、Shimono Akihiko、Yonemura Yuji、Kawaguchi Tatsuya、Chiba Shigeru、Kanakura Yuzuru、Nishimura Jun-Ichi、Ninomiya Haruhiko、Obara Naoshi
    • Journal Title

      International Journal of Hematology

      Volume: 115 Issue: 4 Pages: 470-480

    • DOI

      10.1007/s12185-022-03287-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pegcetacoplan versus Eculizumab in PNH2021

    • Author(s)
      Yasutaka Ueda, Hiroyuki Takamori, Jun-Ichi Nishimura
    • Journal Title

      New England Journal of Medicine

      Volume: 385 Issue: 18 Pages: 1723-1726

    • DOI

      10.1056/nejmc2106424

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Disseminated Gonococcal Infection in a Japanese Man with Complement 7 deficiency with compound heterozygous variants.2021

    • Author(s)
      Kageyama, M., Hagiya, H., Ueda, Y., Ohtani, K., Fukumori, Y., Inoue, N., Wakamiya, N., Yoneda, N., Kimura, K., Nagasawa, M., Nakagami, F., Nishi, I., Sugimoto, K., Rakugi H.
    • Journal Title

      Medicine

      Volume: 100 Issue: 13 Pages: e25265-e25265

    • DOI

      10.1097/md.0000000000025265

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The clinical significance of PNH-phenotype cells accounting for < 0.01% of total granulocytes detected by the Clinical and Laboratory Standards Institute methods in patients with bone marrow failure2021

    • Author(s)
      Hosokawa Kohei、Ishiyama Ken、Ikemoto Toshiyuki、Sugimori Chiharu、Noji Hideyoshi、Shichishima Tsutomu、Obara Naoshi、Chiba Shigeru、Ninomiya Haruhiko、Nguyen Mai Anh Thi、Shirasugi Yukari、Nakamura Yoshihiko、Ando Kiyoshi、Ueda Yasutaka et al.
    • Journal Title

      Annals of Hematology

      Volume: 100 Issue: 8 Pages: 1975-1982

    • DOI

      10.1007/s00277-020-04314-w

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Donor stem cell‐derived paroxysmal nocturnal hemoglobinuria after umbilical cord blood transplantation2020

    • Author(s)
      Nakaya Yosuke、Nakao Takafumi、Ueda Yasutaka、Takamori Hiroyuki、Nishimura Jun‐Ichi、Tatsumi Naoko、Tsutsumi Minako、Yoshida Masahiro、Yoshimura Takuro、Hayashi Yoshiki、Yamane Takahisa
    • Journal Title

      European Journal of Haematology

      Volume: 105 Issue: 5 Pages: 659-661

    • DOI

      10.1111/ejh.13498

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation.2019

    • Author(s)
      Hochsmann B, Murakami Y, Osato M, Knaus A, Kawamoto M, Inoue N, Hirata T, Murata S, Anliker M, Eggermann T, Jager M, Floettmann R, Hollein A, Murase S, Ueda Y, Nishimura JI, Kanakura Y, Kohara N, Schrezenmeier H, Krawitz PM, Kinoshita T.
    • Journal Title

      The Journal of Clinical Investigation

      Volume: 129 Issue: 12 Pages: 5123-5136

    • DOI

      10.1172/jci123501

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Clinical Significance of Small PNH-Type Cell Populations in Bone Marrow Failure Syndromes - an Interim Analysis of Japanese Multicentrer Prospective Study -2021

    • Author(s)
      Yasutaka Ueda, Kohei Hosokawa, Ken Ishiyama, Hiroyuki Takamori, Yuji Yonemura, Naoshi Obara, Hideyoshi Noji, Kiyoshi Ando, Tsutomu Shichishima, Takayuki Ikezoe, Shigeru Chiba, Haruhiko Ninomiya, Tatsuya Kawaguchi , Jun-ichi Nishimura , Yuzuru Kanakura and Shinji Nakao
    • Organizer
      63rd American Society of Hematology Annual Meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clinically Important Difference for the FACIT-Fatigue Scale in Paroxysmal Nocturnal Hemoglobinuria: A Derivation from International PNH Registry Patient Data2021

    • Author(s)
      David Cella, Peter Johansson, Yasutaka Ueda, Ioannis Tomazos, Philippe Gustovic, Alice Wang, Ami S. Patel, and Hubert Schrezenmeier
    • Organizer
      63rd American Society of Hematology Annual Meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Inflammation and Fatigue in Patients With Cold Agglutinin Disease (CAD): Analysis From the Phase 3 CARDINAL Study2021

    • Author(s)
      Ilene Weitz,Yasutaka Ueda, Frank Shafer, Jun Su,Meredith Foster, Michael Storek, Parija Patel
    • Organizer
      European Hematology Association congress 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Effectiveness of eculizumab treatment in patients aged >65 years with paroxysmal nocturnal hemoglobinuria (PNH): results from the International PNH Registry2020

    • Author(s)
      Jong Wook Lee, Yasutaka Ueda, Philippe Gustovic, Ke Zu, Alexander Kulagin, Morag Griffin
    • Organizer
      25th European Hematology Association (EHA) 2020 Congress
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cold Agglutinin Disease (CAD) Real World Evidence (CADENCE) Registry: Design of the First International, Prospective CAD Registry2020

    • Author(s)
      Alexander Roth, Ulrich Jager, Bernd Jilma, Wilma Barcellini, Anita Hill, Quentin Hill, David J. Kuter,Catherine M. Broome, Marc Michel, Sacha Sergio Zeerleder, Yasutaka Ueda, Jaime Morales Arias, Jun Su, Sjgbjorn Berentsen
    • Organizer
      25th European Hematology Association (EHA) 2020 Congress
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] An Optimized Crovalimab Dose and Regimen Reduced the Formation of Drug-Target-Drug Complexes in Patients with Paroxysmal Nocturnal Hemoglobinuria from the Phase I/II COMPOSER Trial2020

    • Author(s)
      Nishimura J, Soubret A, Buatois S, Charoin JE, Sreckovic S, Bucher C, Hernandez-Sanchez J,Jordan G, Ramos J, Arase N,Hotta M, Isaka Y, Ito Y, Kanakura Y, Kim JS, Kinoshita T, Morii E, Panse J, De Latour RP, Roth A, Schrezenmeier H, Sica S, Takamori H, Ueda Y et al
    • Organizer
      62nd American Society of Hematology Annual Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cold Agglutinin Disease (CAD) Real-World Evidence (CADENCE) Registry: Design of the First International, Prospective CAD Registry2020

    • Author(s)
      Alexander Roth, Ulrich Jaeger, Bernd Jilma, Wilma Barcellini, Anita Hill, Quentin Hill, David J. Kuter, Catherine M. Broome, Marc Michel, Sacha Sergio Zeerleder, Yasutaka Ueda, Jaime Morales-Arias, Jun Su and Sjgbjorn Berentsen
    • Organizer
      62nd American Society of Hematology Annual Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Inflammation and Fatigue in Patients with Cold Agglutinin Disease (CAD): Analysis from the Phase 3 Cardinal Study2020

    • Author(s)
      Ilene C. Weitz, Yasutaka Ueda, Frank Shafer, Jun Su, Meredith Foster, Michael Storek and Parija Patel
    • Organizer
      62nd American Society of Hematology Annual Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] THE RELATIONSHIP BETWEEN THE PRETREATMENT PNH CLONE SIZE AND CLINICAL COURSE IN PATIENTS WITH BONE MARROW FAILURE SYNDROMES: INTERIM ANALYSIS OF JAPANESE MULTICENTER PROSPECTIVE STUDY2019

    • Author(s)
      Yasutaka Ueda, Kohei Hosokawa, Ken Ishiyama, Hiroyuki Takamori, Yuji Yonemura, Naoshi Obara, Hideyoshi Noji, Hiroshi Takahashi, Yukari Shirasugi, Takahisa Matsuda, Kiyoshi Ando, Tsutomu Shichishima, Takayuki Ikezoe, Shigeru Chiba, Haruhiko Ninomiya, Tatsuya Kawaguchi, Jun-ichi Nishimura, Yuzuru Kanakura, Shinji Nakao
    • Organizer
      24th Congress of European Hematology Association
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2023-01-30  

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