Development of novel cancer immunotherapy using anti-CCR4 mAb combined with immunomodulatory agents

• Project/Area Number: 20790680
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Nagoya City University
• Principal Investigator: ISHIDA Takashi Nagoya City University, 大学院・医学研究科, 講師 (80405183)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: CCR4 / 抗体療法 / lymphoma / ADCC / NOGマウス / 成人T細胞白血病リンパ腫(ATL)

Research Abstract

There is a lack of suitable small animal models to evaluate human ADCC in vivo, because of the species incompatibility between humans and animals or due to nonspecific allogeneic immune reactions. To overcome these problems, we established a human tumor-bearing mouse model, using NOG mice as recipients, in which autologous human immune cells are engrafted and mediate ADCC but in which endogenous murine cells are unable to mediate ADCC. We demonstrate significant antitumor activity in vivo associated with robust ADCC mediated by autologous effector cells from the same patients. The present study is the first to report a mouse model in which a potent antitumor effect of the therapeutic mAb against primary tumor cells is mediated by autologous human immune cells. This approach makes it possible to model the human immune system active in Ab-based cancer immunotherapy including combination treatment in vivo, and thus to perform more appropriate preclinical evaluations of novel therapeutic mAb.

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, lida S, Imada K, Uchiyama T, Akinaga S, Shi tara 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: 1591-1598
  • 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
  • NAID: 10025142727
  • 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] Defucosylated anti-CCR4 monoclonal antibody exerts potent ADCC against primary ATLL Cells mediated by autologous human immune cells in NOD/Shi-scid, IL-2 Rgamma(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, lida S, Inagaki H, Ueda R.
  • Journal Title: J Immunol. 183 Pages: 4782-4791
  • 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, lida 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: 3325-3328
  • 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, et.al.
  • Journal Title: Int J Cancer (Epub ahead of print)
  • 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
  • NAID: 10024013572
  • 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
• [Journal Article] Augmentation of antitumour activity of defucosylated chimeric anti-CCR4 monocl onal antibody in SOD mouse model of adult T-cell leukaemia/lymphoma using G-CSF (2008)
  • Author(s): Yano H, Ishida T, et.al.
  • Journal Title: Br J Haematol 140 Pages: 586-589
  • Peer Reviewed
• [Journal Article] Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomera se I inhibitor, irinotecan (CPT-11), for multiple myeloma (2008)
  • Author(s): Yano H, Ishida T, et.al.
  • Journal Title: Cancer Sci 99 Pages: 2309-2314
  • Peer Reviewed
• [Journal Article] Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated an titumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null)mouse model (2008)
  • Author(s): Ito A, Ishida T, et.al.
  • Journal Title: Cancer Immunol Immunother (Epub ahead of print)
  • 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 (2008)
  • Author(s): Ri M, Ishida T, et.al.
  • Journal Title: Cancer Sci (Epub ahead of print)
  • NAID: 10025142727
  • Peer Reviewed
• [Presentation] Clinical Significance of Serum TARC/CCL17 in ATLL Patients : High TARC/CCL17 Level Is a Significant Unfavorable Prognostic Factor (2008)
  • Author(s): Atsushi Inagaki, Takashi Ishida, et.al.
  • Organizer: The American Society of Hematology 50th Annual Meeting And Exposition, SAN FRANCISCO CA, MOSCONE CENTER
  • Place of Presentation: SAN FRANCISCO
  • Year and Date: 2008-12-08
• [Book] 抗体による癌の治療抗体実験マニュアル (2008)
  • Author(s): 高津聖志、三宅健介、山元弘、瀧伸介編集
  • Total Pages: 257
  • Publisher: 羊土社