日本学士院

会員情報

 

氏名

上田龍三（うえだ　りゅうぞう）

 

所属部・分科

第2部第7分科

選定年月日

令和6年12月12日

専攻学科目

内科学・臨床腫瘍学・血液腫瘍学

現職等

名古屋大学大学院医学系研究科特任教授
名古屋市立大学名誉教授
愛知医科大学名誉教授

受賞等

〔国内〕

〔海外〕



外国アカデミー会員等

主要な学術上の業績

上田龍三氏は、成人T細胞白血病・リンパ腫（ATLL）に対する画期的な日本初の抗がん抗体医薬の開発研究に成功したのみならず、長年に亘り、がんの基礎研究成果を臨床に導入する「がんトランスレーショナル・リサーチ（TR）」の発展に貢献しました。

ATLLは1977年に日本で発見された治療困難な血液のがんです。ATLLの病態、発症原因、感染経路などの研究は、卓越した日本の研究者により次々と全貌が明らかにされましたが、治療法の開発研究は皆無でした。

上田氏は、ATLLの細胞表面にあるCCR4分子がATLLの特異的マーカー分子であり、予後不良因子であることを見いだし、同分子を標的とした抗体医薬の開発に着手しました。前臨床研究を踏まえて、自ら臨床開発の統括責任医師としてFirst in Human（FIH）の治験から主導し、臨床的有用性を証明しました。2012年に薬事承認され、ATLL患者の第一治療選択薬となりました。この一連の取り組みは、抗体作製、前臨床研究、治験、薬事承認、コンパニオン診断薬開発に至る産学共同研究の新しい方向性を示しました。

主要な著書・論文

原著

  1. 1. Ueda R, Shiku H, Pfreundschuh M, Takahashi T, Li ITC, Whitmore WF, Oettgen HF, Old LJ: Cell surface antigens of human renal cancer defined by autologous typing.
    J Exp Med, 150 (3): 564-579, 1979.
  2. Ueda R, Ogata S, Morrissey DM, Finstad CL, Szkudlarek J, Whitmore WF, Oettgen HF., Lloyd KO. Old LJ.: Cell surface antigens of human renal cancer defined by mouse monoclonal antibodies: Identification of tissue-specific kidney glycoproteins. Proc Natl Acad Sci USA, 78 (8): 5122-5126, 1981.
  3. Ueda R, Tanimoto M, Takahashi T, Ogata S, Nishida K, Namikawa R, Nishizuka Y, Ota K: Serological analysis of cell surface antigens of null cell acute lymphocytic leukemia by mouse monoclonal antibodies. Proc Natl Acad Sci USA, 79 (14): 4386-4390, 1982.
  4. Ueda R, Nishida K, Koide Y, Tsuge I, Seto M, Yoshida M, Miyoshi I, Ota K, Takahashi T: Two mouse monoclonal antibodies detecting two different epitopes of an activated lymphocyte antigen on adult T-cell leukemia cells. Cancer Res, 45 (3): 1314-1319, 1985.
  5. Takahashi T, Ueda R, Song X, Nishida K, Shinzato M, Namikawa R, Ariyoshi Y, Ota K, Kato K, Nagatsu T, Imaizumi M, Abe T, Takahashi T: Two novel cell surface antigens on small cell lung carcinoma defined by mouse monoclonal antibodies NE-25 and PE-35. Cancer Res, 46 (9): 4770-4775, 1986.
  6. Motoi T, Uchiyama T, Hori T, Itoh K, Uchino H, Ueda R: Elevated serum-soluble interleukin-2 receptor (Tac antigen) levels in chronic myelogenous leukemia patients with blastic crisis. Blood, 74 (3): 1052-1057, 1989.
  7. Takahahsi T, Takahashi T, Suzuki H, Hida T, Sekido Y, Ariyoshi Y, Ueda R: The p53 gene is very frequently mutated in small-cell lung cancer with a distinct nucleotide substitution pattern. Oncogene, 6 (10): 1775-1778, 1991.
  8. Namikawa R, Ueda R, Kyoizumi S: Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice. Blood, 82 (8): 2526-2536, 1993.
  9. Suzuki H, Ueda R, Takahashi T, Takahashi T: Altered imprinting in lung cancer.  Nat Genet, 6 (4): 332-333, 1994.
  10. Ishida T, Utsunomiya A, Iida S, Inagaki H, Takatsuka Y, Kusumoto S, Takeuchi G, Shimizu S, Ito M, Komatsu H, Wakita A, Eimoto T, Matsushima K, Ueda R:  Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res, 9 (10 Pt 1): 3625-3634, 2003.
  11. Niwa R, Shoji-Hosaka E, Sakurada M, Shinkawa T, Uchida K, Nakamura K, Matsushima K, Ueda R, Hanai N, Shitara K: Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res, 64 (6): 2127-2133, 2004.
  12. Ishida T, Iida S, Akatsuka Y, Ishii T, Miyazaki M, Komatsu H, Inagaki H, Okada N, Fujita T, Shitara K, Akinaga S, Takahashi T, Utsunomiya A, Ueda R: The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-Cell leukemia/lymphoma. Clin Cancer Res, 10 (22): 7529-7539, 2004.
  13. Yano H, Ishida T, Inagaki A, Ishii T, Ding J, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R: Defucosylated anti-CC chemokine receptor 4 monoclonal antibody combined with immunomodulatory cytokines: a novel immunotherapy for aggressive/refractory Mycosis fungoides and Sezary syndrome. Clin Cancer Res, 13 (21): 6494-6500, 2007.
  14. Ito A, Ishida T, Utsunomiya A, Sato F, Mori F, Yano H, Inagaki A, Suzuki S, Takino H, Ri M, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R: Defucosylated anti-CCR4 monoclonal antibody exerts potent ADCC against primary ATLL cells mediated by autologous human immune cells in NOD/Shi-scid, IL-2R gamma(null) mice in vivo. J Immunol, 183 (7): 4782-4791, 2009.
  15. Yamamoto K, Utsunomiya A, Tobinai K, Tsukasaki K, Uike N, Uozumi K, Yamaguchi K, Yamada Y, Hanada S, Tamura K, Nakamura S, Inagaki H, Ohshima K, Kiyoi H, Ishida T, Matsushima K, Akinaga S, Ogura M, Tomonaga M, Ueda R: Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol, 28 (9): 1591-1598, 2010.
  16. Ishida T, Ueda R: Immunopathogenesis of lymphoma: focus on CCR4. Cancer Sci, 102 (1): 44-50, 2011.
  17. Ishida T, Ueda R. Antibody therapy for Adult T-cell leukemia-lymphoma.　Int J Hematol, 94 (5): 443-452, 2011.
  18. Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, Saburi Y, Miyamoto T, Takemoto S, Suzushima H, Tsukasaki K, Nosaka K, Fujiwara H, Ishitsuka K, Inagaki H, Ogura M, Akinaga S, Tomonaga M, Tobinai K, Ueda R:  Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol, 30 (8): 837-842, 2012.
  19. Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, Fujimoto K, Yamamoto K, Miyamoto T, Uike N, Tanimoto M, Tsukasaki K, Ishizawa K, Suzumiya J, Inagaki H, Tamura K, Akinaga S, Tomonaga M, Ueda R: Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol, 32 (11): 1157-1163, 2014.
  20. Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R, Nakayama E: Phase Ia study of FoxP3+ CD4 Treg depletion by Infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients. Clin Cancer Res, 21 (19): 4327-4336, 2015.
  21. Sakamoto Y, Ishida T, Masaki A, Murase T, Yonekura K, Tashiro Y, Tokunaga M, Utsunomiya A, Ito A, Kusumoto S, Iida S, Ueda R, Inagaki H: CCR4 mutations associated with superior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment. Blood, 132 (7): 758-761, 2018.
  22. Maeda Y, Wada H, Sugiyama D, Saito T, Irie T, Itahashi K, Minoura K, Suzuki S, Kojima T, Kakimi K, Nakajima J, Funakoshi T, Iida S, Oka M, Shimamura T, Doi T, Doki Y, Nakayama E, Ueda R, Nishikawa H: Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab. Nat Commun, 12 (1): 7280, 2021.
  23. Fujikawa K, Saito T, Kurose K, Kojima T, Funakoshi T, Sato E, Kakimi K, Iida S, Doki Y, Oka M, Ueda R, Wada H. Integrated analysis of phase 1a and 1b randomized controlled trials; Treg-targeted cancer immunotherapy with the humanized anti-CCR4 antibody, KW-0761, for advanced solid tumors. PLoS One. Sep 20;18(9): e0291772, 2023.

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