The scientific clinical study of antibody therapy

2009 Fiscal Year Final Research Report

• Project/Area Number: 17016065
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Nagoya City University
• Principal Investigator: UEDA Ryuzo Nagoya City University, 大学院・医学研究科, 教授 (20142169)
• Co-Investigator(Kenkyū-buntansha): SATO Shigeki 名古屋市立大学, 大学院・医学研究科, 准教授 (80254283) ; KOMATSU Hirokazu 名古屋市立大学, 大学院・医学研究科, 准教授 (60336675) ; ISHIDA Takashi 名古屋市立大学, 大学院・医学研究科, 講師 (80405183)
• Project Period (FY): 2005 – 2009
• Keywords: 抗体療法 / CCR4 / ADCC / 成人T細胞白血病リンパ腫(ATL)

Research Abstract

CCR4 is a chemokine receptor selectively expressed on Treg and Th2 cells. Because we previously found that CCR4 is expressed on certain types of T-cell leukemia/lymphoma, we postulated that this molecule might represent a novel molecular target for immunotherapy against refractory T-cell leukemia/lymphoma. Accordingly, we have developed a next-generation anti-CCR4 mAb, the Fc region of which is defucosylated, resulting in highly enhanced ADCC. Based on our laboratory work on CCR4, and as an outcome of the success of this translational research, we have completed phase I & II clinical trials of anti-CCR4 mAb in patients with CCR4-positive T-cell leukemia/lymphoma in Japan, and are in the process of preparing an application to the regulatory authority for approval.

Research Products

• [Journal Article] Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma (ATLL). (2010)
  • Author(s): Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, Iida S, Imada K, Uchiyama T, Akinaga S, Shitara K, Ueda R
  • Journal Title: Clin Cancer Res. 16 Pages: 1520-1531
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: J Clin Oncol. 28 Pages: 1591-8
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: J Immunol. 183 Pages: 4782-91
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Blood 114 Pages: 3325-8
  • Peer Reviewed
• [Journal Article] Expression of the ULBP ligands for NKG2D by B-NHL cells plays an important role in determining their susceptibility to rituximab-induced ADCC. (2009)
  • Author(s): Inagaki A, Ishida T, Yano H, Ishii T, Kusumoto S, Ito A, Ri M, Mori F, Ding J, Komatsu H, Iida S, Ueda R
  • Journal Title: Int J Cancer 125 Pages: 212-21
  • Peer Reviewed
• [Journal Article] Bortezomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1. (2009)
  • Author(s): Ri M, Iida S, Ishida T, Ito A, Yano H, Inagaki A, Ding J, Kusumoto S, Komatsu H, Utsunomiya A, Ueda R
  • Journal Title: Cancer Sci. 100 Pages: 341-8
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Cancer Immunol Immunother 58 Pages: 1195-206
  • Peer Reviewed
• [Journal Article] Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma. (2008)
  • Author(s): 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
  • Journal Title: Cancer Sci. 99 Pages: 2309-14
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Yano H, Ishida T, Imada K, Sakai T, Ishii T, Inagaki A, Iida S, Uchiyama T, Ueda R
  • Journal Title: Br J Haematol 140 Pages: 586-9
  • Peer Reviewed
• [Journal Article] Defucosylated anti -CCR4 monoclonal antibody combined with immunomodulatory cytokines: a novel immunotherapy for aggressive/ refractory mycosis fungoides and sezary syndrome. (2007)
  • Author(s): Yano H, Ishida T, Inagaki A, Ishii T, Ding J, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R
  • Journal Title: Clin Cancer Res. 13 Pages: 6494-500
  • Peer Reviewed
• [Journal Article] Regulatory T-cell Function of adult T-cell leukemia/lymphoma cells. (2007)
  • Author(s): Yano H, Ishida T, Inagaki A, Ishii T, Kusumoto S, Komatsu H, Iida S, Utsunomiya A, Ueda R
  • Journal Title: Int J Cancer 120 Pages: 2052-7
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: J Clin Oncol. 25 Pages: 5458-64
  • Peer Reviewed
• [Journal Article] Prognostic Significance of NPM-ALK Fusion Transcript Overexpression in ALK-positive Anaplastic Large Cell Lymphoma. (2007)
  • Author(s): Li C, Takino H, Eimoto T, Ishida T, Inagaki A, Ueda R, Suzuki R, Yoshino T, Nakagawa A, Nakamura S, Inagaki H
  • Journal Title: Mod Pathol 20 Pages: 648-55
  • Peer Reviewed
• [Journal Article] Clinical Significance of a blood eosinophilia in adult T-cell leukemia/lymphoma: a blood eosinophilia is a significant unfavorable prognostic factor. (2007)
  • Author(s): Utsunomiya A, Ishida T, Inagaki A, Ishii T, Yano H, Komatsu H, Iida S, Yonekura K, Takeuchi S, Takatsuka Y, Ueda R
  • Journal Title: Leuk Res. 31 Pages: 915-20
  • Peer Reviewed
• [Journal Article] The CCR4 as a novel specific molecular target for immunotherapy in Hodgkin lymphoma. (2006)
  • Author(s): Ishida T, Ishii T, Inagaki A, Yano H, Kusumoto S, Ri M, Komatsu H, Iida S, Inagaki H, Ueda R
  • Journal Title: Leukemia 20 Pages: 2162-8
  • Peer Reviewed
• [Journal Article] CCR4 as a novel molecular target for immunotherapy of cancer. (2006)
  • Author(s): Ishida T, Ueda R
  • Journal Title: Cancer Sci. 97 Pages: 1139-46
  • Peer Reviewed
• [Journal Article] Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. (2006)
  • Author(s): Ishida T, Ishii T, Inagaki A, Yano H, Komatsu H, Iida S, Inagaki H, Ueda R
  • Journal Title: Cancer Res. 66 Pages: 5716-22
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Inagaki A, Ishida T, Ishii T, Komatsu H, Iida S, Ding J, Yonekura K, Takeuchi S, Takatsuka Y, Utsunomiya A, Ueda R
  • Journal Title: Int J Cancer 118 Pages: 3054-61
  • Peer Reviewed
• [Journal Article] Introduction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor. (2006)
  • Author(s): Sanda T, Asamitsu K, Ogura H, Iida S, Utsunomiya A, Ueda R., Okamoto, T
  • Journal Title: Leukemia 20 Pages: 590-8
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Niwa R, Sakurada M, Kobayashi Y, Uehara A, Matsushima K, Ueda R, Nakamura K, Shitara K
  • Journal Title: Clin Cancer Res. 11 Pages: 2327-36
  • Peer Reviewed
• [Journal Article] Mechanisms for the apoptosis of small cell lung cancer cells induced by anti-GD2 monoclonal antibodies: Roles of anoikis. (2005)
  • Author(s): Aixinjueluo W, Furukawa K, Zhang Q, Hamamura K, Tokuda N, Yoshida S, Ueda R., Furukawa K.
  • Journal Title: J Biol Chem. 280 Pages: 29828-36
  • Peer Reviewed
• [Journal Article] Production and characterization of an active single-chain variable fragment antibody recognizing CD25. (2005)
  • Author(s): Muramatsu H, Yoshikawa K, Hayashi T, Takasu S, Kawada Y, Uchida K, Sato S, Takahashi T, Saga S, Ueda R
  • Journal Title: Cancer Lett. 225 Pages: 225-36
  • Peer Reviewed
• [Presentation] CCR4 as a novel specific molecular target for immunotherapy in ATLL. (2010)
  • Author(s): Ueda R
  • Organizer: 8th AACR/JCB Conference
  • Place of Presentation: Waikoloa, Hawaii
  • Year and Date: 20100205-20100209
• [Presentation] 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)
  • Author(s): Yamamoto K, Tobinai K, Utsunomiya A, Tsukasaki K, Uike N, Uozumi K, Tomonaga M, Matsushima K, Shitara K, Akinaga S, Ueda R
  • Organizer: The 50th Annual Meeting of American Society of Hematology
  • Place of Presentation: San Francisco, CA, USA.
  • Year and Date: 20081200