Identification of the most appropriate therapeutic target for PNH

• Project/Area Number: 19K08862
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Osaka 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: ¥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。

Research Products

• [Journal Article] Long-term follow-up of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: post-marketing surveillance in Japan (2022)
  • 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
  • Peer Reviewed
• [Journal Article] Pegcetacoplan versus Eculizumab in PNH (2021)
  • 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
  • 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
  • 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 failure (2021)
  • 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
  • Peer Reviewed
• [Journal Article] Donor stem cell‐derived paroxysmal nocturnal hemoglobinuria after umbilical cord blood transplantation (2020)
  • 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
  • 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
  • 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
  • Int'l Joint Research
• [Presentation] Clinically Important Difference for the FACIT-Fatigue Scale in Paroxysmal Nocturnal Hemoglobinuria: A Derivation from International PNH Registry Patient Data (2021)
  • 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
  • Int'l Joint Research
• [Presentation] Inflammation and Fatigue in Patients With Cold Agglutinin Disease (CAD): Analysis From the Phase 3 CARDINAL Study (2021)
  • Author(s): Ilene Weitz,Yasutaka Ueda, Frank Shafer, Jun Su,Meredith Foster, Michael Storek, Parija Patel
  • Organizer: European Hematology Association congress 2021
  • Int'l Joint Research
• [Presentation] Effectiveness of eculizumab treatment in patients aged >65 years with paroxysmal nocturnal hemoglobinuria (PNH): results from the International PNH Registry (2020)
  • Author(s): Jong Wook Lee, Yasutaka Ueda, Philippe Gustovic, Ke Zu, Alexander Kulagin, Morag Griffin
  • Organizer: 25th European Hematology Association (EHA) 2020 Congress
  • Int'l Joint Research
• [Presentation] Cold Agglutinin Disease (CAD) Real World Evidence (CADENCE) Registry: Design of the First International, Prospective CAD Registry (2020)
  • 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
  • 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 Trial (2020)
  • 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
  • Int'l Joint Research
• [Presentation] Cold Agglutinin Disease (CAD) Real-World Evidence (CADENCE) Registry: Design of the First International, Prospective CAD Registry (2020)
  • 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
  • Int'l Joint Research
• [Presentation] Inflammation and Fatigue in Patients with Cold Agglutinin Disease (CAD): Analysis from the Phase 3 Cardinal Study (2020)
  • 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
  • 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 STUDY (2019)
  • 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
  • Int'l Joint Research