抗体療法の科学的臨床研究

2009 年度 研究成果報告書

• 研究課題/領域番号: 17016065
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 17016065
• 研究代表者: 上田 龍三 17016065, 大学院・医学研究科, 教授 (20142169)
• 研究分担者: 佐藤 滋樹 名古屋市立大学, 大学院・医学研究科, 准教授 (80254283) ; 小松 弘和 名古屋市立大学, 大学院・医学研究科, 准教授 (60336675) ; 石田 高司 名古屋市立大学, 大学院・医学研究科, 講師 (80405183)
• 研究期間 (年度): 2005 – 2009
• キーワード: 抗体療法 / CCR4 / ADCC / 成人T細胞白血病リンパ腫(ATL)

研究概要

ケモカインレセプターCCR4が難治性T細胞性リンパ腫に特異的に発現していることを見出し、CCR4に対する低フコース型治療抗体の抗腫瘍効果をin vitro及びin vivoで示した。の開発研究を行った。さらに、これらの前臨床研究を基盤とし、CCR4陽性末梢性T 細胞性リンパ腫患者を対象としたフコース除去ヒト化抗CCR4抗体 (KW-0761)の第I相及び第II 相臨床試験を欧米諸国に先駆け日本で実施、本薬剤の承認申請のための臨床データを得た。

研究成果

• [雑誌論文] Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma (ATLL). (2010)
  • 著者名/発表者名: Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, Iida S, Imada K, Uchiyama T, Akinaga S, Shitara K, Ueda R
  • 雑誌名: Clin Cancer Res. 16 ページ: 1520-1531
  • 査読あり
• [雑誌論文] 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. (2010)
  • 著者名/発表者名: 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
  • 雑誌名: J Clin Oncol. 28 ページ: 1591-8
  • 査読あり
• [雑誌論文] Defucosylated anti-CCR4 monoclonal antibody exerts potent ADCC against primary ATLL Cells mediated by autologous human immune cells in NOD/Shi-scid, IL-2Rgamma(null) mice in vivo. (2009)
  • 著者名/発表者名: 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
  • 雑誌名: J Immunol. 183 ページ: 4782-91
  • 査読あり
• [雑誌論文] The Asn505 mutation of c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity. (2009)
  • 著者名/発表者名: Ding J, Komatsu H, Iida S, Yano H, Kusumoto S, Inagaki A, Mori F, Ri M, Ito A, Wakita A, Ishida T, Nitta M, Ueda R
  • 雑誌名: Blood 114 ページ: 3325-8
  • 査読あり
• [雑誌論文] Expression of the ULBP ligands for NKG2D by B-NHL cells plays an important role in determining their susceptibility to rituximab-induced ADCC. (2009)
  • 著者名/発表者名: Inagaki A, Ishida T, Yano H, Ishii T, Kusumoto S, Ito A, Ri M, Mori F, Ding J, Komatsu H, Iida S, Ueda R
  • 雑誌名: Int J Cancer 125 ページ: 212-21
  • 査読あり
• [雑誌論文] Bortezomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1. (2009)
  • 著者名/発表者名: Ri M, Iida S, Ishida T, Ito A, Yano H, Inagaki A, Ding J, Kusumoto S, Komatsu H, Utsunomiya A, Ueda R
  • 雑誌名: Cancer Sci. 100 ページ: 341-8
  • 査読あり
• [雑誌論文] Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model. (2009)
  • 著者名/発表者名: Ito A, Ishida T, Yano H, Inagaki A, Suzuki S, Sato F, Takino H, Mori F, Ri M, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R
  • 雑誌名: Cancer Immunol Immunother 58 ページ: 1195-206
  • 査読あり
• [雑誌論文] Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma. (2008)
  • 著者名/発表者名: Yano H, Kayukawa S, Iida S, Nakagawa C, Oguri T, Sanda T, Ding J, Mori F, Ito A, Ri M, Inagaki A, Kusumoto S, Ishida T, Komatsu H, Inagaki H, Suzuki A, Ueda R
  • 雑誌名: Cancer Sci. 99 ページ: 2309-14
  • 査読あり
• [雑誌論文] Augmentation of antitumour activity of defucosylated chimeric anti-CCR4 monoclonal antibody in SCID mouse model of adult T-cell leukaemia/lymphoma using G-CSF. (2008)
  • 著者名/発表者名: Yano H, Ishida T, Imada K, Sakai T, Ishii T, Inagaki A, Iida S, Uchiyama T, Ueda R
  • 雑誌名: Br J Haematol 140 ページ: 586-9
  • 査読あり
• [雑誌論文] Defucosylated anti -CCR4 monoclonal antibody combined with immunomodulatory cytokines: a novel immunotherapy for aggressive/ refractory mycosis fungoides and sezary syndrome. (2007)
  • 著者名/発表者名: Yano H, Ishida T, Inagaki A, Ishii T, Ding J, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R
  • 雑誌名: Clin Cancer Res. 13 ページ: 6494-500
  • 査読あり
• [雑誌論文] Regulatory T-cell Function of adult T-cell leukemia/lymphoma cells. (2007)
  • 著者名/発表者名: Yano H, Ishida T, Inagaki A, Ishii T, Kusumoto S, Komatsu H, Iida S, Utsunomiya A, Ueda R
  • 雑誌名: Int J Cancer 120 ページ: 2052-7
  • 査読あり
• [雑誌論文] Japan Clinical Oncology Group Study JCOG9801. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. (2007)
  • 著者名/発表者名: Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, Ikeda S, Masuda M, Nagoshi H, Ueda R, Tamura K, Sano M, Momita S, Yamaguchi K, Kawano F, Hanada S, Tobinai K, Shimoyama M, Hotta T, Tomonaga M
  • 雑誌名: J Clin Oncol. 25 ページ: 5458-64
  • 査読あり
• [雑誌論文] Prognostic Significance of NPM-ALK Fusion Transcript Overexpression in ALK-positive Anaplastic Large Cell Lymphoma. (2007)
  • 著者名/発表者名: Li C, Takino H, Eimoto T, Ishida T, Inagaki A, Ueda R, Suzuki R, Yoshino T, Nakagawa A, Nakamura S, Inagaki H
  • 雑誌名: Mod Pathol 20 ページ: 648-55
  • 査読あり
• [雑誌論文] Clinical Significance of a blood eosinophilia in adult T-cell leukemia/lymphoma: a blood eosinophilia is a significant unfavorable prognostic factor. (2007)
  • 著者名/発表者名: Utsunomiya A, Ishida T, Inagaki A, Ishii T, Yano H, Komatsu H, Iida S, Yonekura K, Takeuchi S, Takatsuka Y, Ueda R
  • 雑誌名: Leuk Res. 31 ページ: 915-20
  • 査読あり
• [雑誌論文] The CCR4 as a novel specific molecular target for immunotherapy in Hodgkin lymphoma. (2006)
  • 著者名/発表者名: Ishida T, Ishii T, Inagaki A, Yano H, Kusumoto S, Ri M, Komatsu H, Iida S, Inagaki H, Ueda R
  • 雑誌名: Leukemia 20 ページ: 2162-8
  • 査読あり
• [雑誌論文] CCR4 as a novel molecular target for immunotherapy of cancer. (2006)
  • 著者名/発表者名: Ishida T, Ueda R
  • 雑誌名: Cancer Sci. 97 ページ: 1139-46
  • 査読あり
• [雑誌論文] Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. (2006)
  • 著者名/発表者名: Ishida T, Ishii T, Inagaki A, Yano H, Komatsu H, Iida S, Inagaki H, Ueda R
  • 雑誌名: Cancer Res. 66 ページ: 5716-22
  • 査読あり
• [雑誌論文] Clinical significance of serum Th1-, Th2- and regulatory T cells-associated cytokines in adult T-cell leukemia/lymphoma: high interleukin-5 and -10 levels are significant unfavorable prognostic factors. (2006)
  • 著者名/発表者名: Inagaki A, Ishida T, Ishii T, Komatsu H, Iida S, Ding J, Yonekura K, Takeuchi S, Takatsuka Y, Utsunomiya A, Ueda R
  • 雑誌名: Int J Cancer 118 ページ: 3054-61
  • 査読あり
• [雑誌論文] Introduction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor. (2006)
  • 著者名/発表者名: Sanda T, Asamitsu K, Ogura H, Iida S, Utsunomiya A, Ueda R., Okamoto, T
  • 雑誌名: Leukemia 20 ページ: 590-8
  • 査読あり
• [雑誌論文] Enhanced natural killer cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density. (2005)
  • 著者名/発表者名: Niwa R, Sakurada M, Kobayashi Y, Uehara A, Matsushima K, Ueda R, Nakamura K, Shitara K
  • 雑誌名: Clin Cancer Res. 11 ページ: 2327-36
  • 査読あり
• [雑誌論文] Mechanisms for the apoptosis of small cell lung cancer cells induced by anti-GD2 monoclonal antibodies: Roles of anoikis. (2005)
  • 著者名/発表者名: Aixinjueluo W, Furukawa K, Zhang Q, Hamamura K, Tokuda N, Yoshida S, Ueda R., Furukawa K.
  • 雑誌名: J Biol Chem. 280 ページ: 29828-36
  • 査読あり
• [雑誌論文] Production and characterization of an active single-chain variable fragment antibody recognizing CD25. (2005)
  • 著者名/発表者名: Muramatsu H, Yoshikawa K, Hayashi T, Takasu S, Kawada Y, Uchida K, Sato S, Takahashi T, Saga S, Ueda R
  • 雑誌名: Cancer Lett. 225 ページ: 225-36
  • 査読あり
• [学会発表] CCR4 as a novel specific molecular target for immunotherapy in ATLL. (2010)
  • 著者名/発表者名: Ueda R
  • 学会等名: 8th AACR/JCB Conference
  • 発表場所: Waikoloa, Hawaii
  • 年月日: 20100205-20100209
• [学会発表] Phase I study of KW-0761, a Defucosylated Patients(Pts) with Adult T-Cell Leukemia-Lymphoma(ATL) or Peripheral T-Cell Lymphoma(PTCL): Updated Results. (2008)
  • 著者名/発表者名: Yamamoto K, Tobinai K, Utsunomiya A, Tsukasaki K, Uike N, Uozumi K, Tomonaga M, Matsushima K, Shitara K, Akinaga S, Ueda R
  • 学会等名: The 50th Annual Meeting of American Society of Hematology
  • 発表場所: San Francisco, CA, USA.
  • 年月日: 20081200