Molecular-based study for the development of monoclonal antibody therapy in chemokine receptors, CCR4 and CXCR3

• Project/Area Number: 16390280
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagoya City University
• Principal Investigator: UEDA Ryuzo Nagoya City University, Nagoya City University Graduate School of Medical Sciences, Department of Medical Oncology and Immunology, Professor (20142169)
• Co-Investigator(Kenkyū-buntansha): IIDA Shinsuke Nagoya City University Graduate School of Medical Sciences, Department of Medical Oncology and Immunology, Associated professor (50295614) ; KOMATSU Hirokazu Nagoya City University Graduate School of Medical Sciences, Department of Medical Oncology and Immunology, Associated professor (60336675)
• Project Period (FY): 2004 – 2006
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥11,500,000 (Direct Cost: ¥11,500,000); Fiscal Year 2006: ¥2,800,000 (Direct Cost: ¥2,800,000); Fiscal Year 2005: ¥2,800,000 (Direct Cost: ¥2,800,000); Fiscal Year 2004: ¥5,900,000 (Direct Cost: ¥5,900,000)
• Keywords: Chemokine receptors / T-cell Malignancies / Monoclonal antibody therapy / ADCC / Regulartory T-cell / CCR4 / CXCR3 / regulatory T cell / FOXP3 / ケモカインレセプター / CXCR3 / FoxP3 / 低フコース化抗体

Research Abstract

CCR4 was shown to be expressed in many types of T-cell malignancies, especially in adult T-cell leukemia/lymphoma (ATLL), peripheral T-cell lymphoma-unspecified (PTCL-U) and anaplastic large cell lymphoma (ALK negative) and be a significant and independent prognostic marker in ATLL and PTCL-U. Monoclonal antibody for CCR4 presented a strong anti-tumor effect for several types of T-cell malignancies via ADCC activity in vivo as well as in vitro assay, including CCR4-espressing Hodgkin lymphoma and cutaneous T-cell lymphoma. CCR4 was also expressed in the surface of cells with the character of regulatory T-cells (FOXP3 positive), strongly suggesting that the origin of ATLL tumor cells can be regulatory T-cells. Reactive T-cells surrounding Hodgkin cells (Reed-Sternberg cells) were shown to manifest both CCR4 and FOXP3 expressions on their surfaces, which suggest that CCR4 can be target molecule for the elimination of the anergy for tumor immunity. Phase I clinical study of the humanized monoclonal antibody therapy of CCR4 for T-cell malignancies was conducted and was shown to be well-tolerable with clinical resoponse.

Research Products

• [Journal Article] Induction of class II major major histocompatibility complex expression in human multiple myeloma cells by retinoid. (2007)
  • Author(s): Sanda, T.
  • Journal Title: Haematologica 92(1) Pages: 115-20
• [Journal Article] Introduction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor (2006)
  • Author(s): Sanda, T., et al.
  • Journal Title: Leukemia. 20 (4) Pages: 590-598
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Clinical Significance of Serum Th1-, Th2- and Eegulatory T cells-associated Cytokines in Adult T-cell Leukemia/Lymphoma : High Interleuikin-5 and -10 levels are significant unfavorable prognostic factors. (2006)
  • Author(s): Inagaki, H., et al.
  • Journal Title: Int J Cancer. 118 (12) : Pages: 3054-3061
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege (2006)
  • Author(s): Ishida, T., et al.
  • Journal Title: Cancer Res 66 (11) Pages: 5716-5722
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin Lymphoma (2006)
  • Author(s): Ishida, T., et al.
  • Journal Title: Leukemia. 20 (12) Pages: 2162-8
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] CCR4 as a novel molecular targer for imminotherapy of cancer. (2006)
  • Author(s): Ishida, T., et al.
  • Journal Title: Cancer Sci 97 (11) Pages: 1139-46
  • Description: 「研究成果報告書概要(和文)」より
• [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(4) Pages: 590-598
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical Significance of Serum Th1-, Th2and Regulatory T cells-associated Gytokines 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(12) Pages: 3054-3061
  • Description: 「研究成果報告書概要(欧文)」より
• [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., Komatsu, H., Iida, S., Ueda, R.
  • Journal Title: Cancer Res 66(11) Pages: 5716-5722
  • Description: 「研究成果報告書概要(欧文)」より
• [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(12) Pages: 2162-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CCR4 as a novel molecular targer for imminotherapy of cancer. (2006)
  • Author(s): Ishida, T., Ueda, R.
  • Journal Title: Cancer Sci 97(11) Pages: 1139-46
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Specific recruitment of CC chemokine receptor 4-positive regulatory Tcells in Hodgkin lymphoma fosters immune privilege. (2006)
  • Author(s): Ishida, T.
  • Journal Title: Cancer Res. 66(11) Pages: 5716-5722
• [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.
  • Journal Title: Int J Cancer. 118(12) Pages: 3054-3061
• [Journal Article] Introduction of cell death in adult T-cell Leukemia cells by a novel IkappaB kinase inhibitor (2006)
  • Author(s): Sanda, T.
  • Journal Title: Leukemia. 20(4) Pages: 590-598
• [Journal Article] The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin Lymphoma. (2006)
  • Author(s): Ishida, T
  • Journal Title: Leukemia. 20(12) Pages: 2162-8
• [Journal Article] CCR4 as a novel molecular targer for imminotherapy of cancer (2006)
  • Author(s): Ishida, T.
  • Journal Title: Cancer Sci, 97(11) Pages: 1139-46
• [Journal Article] Immunoglobulin V(H) genes in thymic MALT lymphoma are biased toward a restricted repertoire and are frequently unmutated (2006)
  • Author(s): Yoshida, M.
  • Journal Title: J Pathol. 208(3) Pages: 415-422
• [Journal Article] Genomewide Array-based comparative genomic Hybridization analysis of acute promyelocytic leukemia. Genes Chromosomes Cancer (2006)
  • Author(s): Karnan, S.
  • Journal Title: Genes Chromosomes Cancer 45(4) Pages: 420-5
• [Journal Article] A past history of gastric malignant lymphoma (2006)
  • Author(s): Suzuki, T.
  • Journal Title: Carcinogenesis 27(7) Pages: 1391-1397
• [Journal Article] Risk Fsctors of disseminated intravascular coagulation in septic systemic inflammatory response syndrome in nursing home residents (2006)
  • Author(s): Kikuchi, M.
  • Journal Title: Geriatr Gerontol Int 6 Pages: 109-115
• [Journal Article] T1653 mutation in the box alpha increases the risk of hepatocellular carcinoma in patients with chronic hepatitis B virus genotype C infection. (2006)
  • Author(s): Ito, K., Ueda, R., et al.
  • Journal Title: Clin Infect Dis. 42(1) Pages: 1-7
• [Journal Article] Smoking increases the treatment failure for Heliobacter pylori eradication. (2006)
  • Author(s): Suzuki, T., Ueda, R., et al.
  • Journal Title: Am J Med 119(3) Pages: 217-224
• [Journal Article] Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor. (2005)
  • Author(s): Sanda, T., et al.
  • Journal Title: Clin Cancer Res. 11 (5) Pages: 1974-1982
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Enhanced natural killer cell binding and activation by low-fucose lgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density (2005)
  • Author(s): Niwa, R., et al.
  • Journal Title: Clinical Cancer Research. 11 Pages: 2327-2336
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Global real-time quantification/reverse transcription-polymerase chain reaction for detecting proto-oncogenes associated with 14q32 chromosomal translocation in multiple myeloma (2005)
  • Author(s): Tajima, E., et al.
  • Journal Title: Haematologica. 90 (4) Pages: 559-562
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antimyeloma eifects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis (2005)
  • Author(s): Sanda, T., et al.
  • Journal Title: Leukemia. 19 Pages: 901-909
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Multiple myeloma oncogene 1(MUM1) /interferon regulatory factor 4 (IEF4) upregulates monokine induced by interferon-gamma (MIG) gene expression in B-cell malignancy (2005)
  • Author(s): Uranishi, M., et al.
  • Journal Title: Leukemia. 19 (8) Pages: 1471-1478
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a“non-germinal center phenotype" (2005)
  • Author(s): Kusumoto, S., et al.
  • Journal Title: Am J Surg Pathol. 29 (8) Pages: 1067-1073
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] p16/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis. Mod Pathol. (2005)
  • Author(s): Takino, H., et al.
  • Journal Title: Mod. Pathol. 18 (9) Pages: 1187-1192
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Detection of API2-MALT1 fusion transcripts in cytologic speciments of patients with pulmonary mucosa-associated lymphoid tissue lymphoma. (2005)
  • Author(s): Inagaki, H., et al.
  • Journal Title: Int J Hematol. 82 (1) Pages: 59-62
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] CC Chemokine Receptor4 (CCR4)Positive diffuse large B-cell lymphoma involving the skin (2005)
  • Author(s): Ishida, T., et al.
  • Journal Title: A case report. Int J Hematol. 82 (2) Pages: 148-151
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Growth, inhibition of multiple myeloma cells by anovel IkappaB kinase inhibitor. (2005)
  • Author(s): Sanda, T., Iida, S., Ogura, H., Asamitsu, K., Murata, T., Bacon, KB., Ueda, R., Okamoto, T.
  • Journal Title: Clin Cancer Res. 11(5) Pages: 1974-1982
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Enhanced natural killer cell binding and activation by low-fucose lgGl 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: Clinical Cancer Research. 11 Pages: 2327-2336
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Global real-time quantification/reverse transcription-polymerase chain reaction for detecting proto-oncogenes associated with 14q32 chromosomal translocatioi in multiple myeloma. (2005)
  • Author(s): Tajima, E., Uranishi, M., Iida, S., Komatsu, H., Nitta, M., Ueda, R.
  • Journal Title: Haematologica. 90(4) Pages: 559-562
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis. (2005)
  • Author(s): Sanda, T., Kuwano, T., Nakao, S., Iida, S., Ishida, T., Komatsu, H., Shudo, K., Kuwano, M., Ono, M., Ueda, R.
  • Journal Title: Leukemia 19 Pages: 901-909
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Multiple myeloma oncogene 1(MUM1) /interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-gamma(MIG) gene expression in B-cell malignancy. (2005)
  • Author(s): Uranishi, M., Iida, S., Sanda, T., Ishida, T., Tajima, E., Ito, M., Komatsu, H., Inagaki, H., Ueda, R.
  • Journal Title: Leukemia 19(8) Pages: 1471-1478
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a " non-germinal center phenotype". (2005)
  • Author(s): Kusumoto, S., Kobayashi, Y., Sekiguchi, N., Tanimoto, K., Onishi, Y., Yokota, Y, Watanabe, T., Maeshima, A. M., Ishida, T., Inagaki, H., Matsuno, Y, Ueda, R., Tobinai, K.
  • Journal Title: Am J Surg Pathol 29(8) Pages: 1067-1073
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] pl6/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis. (2005)
  • Author(s): Takino, H., Okabe, M., Li, C, Ohshima, K., Yoshino, T., Nakamura, S., Ueda, R., Eimoto, T., Inagaki, H.
  • Journal Title: Mod Pathol 18(9) Pages: 1187-1192
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Detection of API2-MALT1 fusion transcripts in cytologic speciments of patients with pulmonary mucosa-associated lymphoid tissue lymphoma. (2005)
  • Author(s): Inagaki, EL, Li, C, Okabe, M., Nishikawa, M., Niimi, T., Iida, S., Ueda, R.
  • Journal Title: Int J Hematol 82(1) Pages: 59-62
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CC Chemokine Receptor4 (CCR4) Positive diffuse large B-cell lymphoma involving the skin: A case report. (2005)
  • Author(s): Ishida, T., Inagaki, H., Kusumoto, S., inagaki, A., Komatsu, H., Iida, S., Hadara, S., Takeuchi, G., Ueda, R.
  • Journal Title: Int J Hematol 82(2) Pages: 148-151
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Enhanced natural killer cell binding and activation by low-fucose lgGl antibody results in potent antibody-dependent cellular cytoxicity induction at lower antigen desity. (2005)
  • Author(s): Niwa, R., Ueda, R., et al.
  • Journal Title: Clinical Cancer Res.2005 11 Pages: 2327-2336
• [Journal Article] Multiple myeloma oncogenge 1(MUMI)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-gamma(MIG) genge expression in B-cell malignancy. (2005)
  • Author(s): Uranishi, M., Ueda, R., et al.
  • Journal Title: Leukemia. 19(8) Pages: 1471-1478
• [Journal Article] CC chemonkine receptor4(CCR4) positive diffuse large B-cell lymphoma involving the skin: A case report. (2005)
  • Author(s): Ishida, T., Ueda, R., et al.
  • Journal Title: Int J Hematol. 82(2) Pages: 148-151
• [Journal Article] Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent celluar cytotoxicify shows potent therapeutic activity to T-cell lexikemia and lymphoma (2004)
  • Author(s): Niwa, R., et al.
  • Journal Title: Cancer Res. 64 (6) Pages: 2127-2133
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] CXC chemokine receptor 3 and CC chemokine receptor 4 expression in T-cell and NK-cell lymphomas with special reference to clinicopathological significance for preripheral T-cell lymphoma, unspecified. (2004)
  • Author(s): Ishida, T., et al.
  • Journal Title: Clin. Cancer Res. 10 (16) Pages: 5494-5500
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Distribution of CXCR3-or CCR4-positive cells in interstitial pneitmonia associated with primary Sjogren's syndrome. (2004)
  • Author(s): Shimizu, S., et al.
  • Journal Title: Virchows Arch 445 (5) Pages: 477-484
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lyinphoma. (2004)
  • Author(s): Ishida, T., et al.
  • Journal Title: Clin. Cancer Res. 10 (22) Pages: 7529-7539
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gastric MALT lymphomas are divided into three groups based on responsiveness to Helicobacter Pylori eradication and detection of API2-MALT1 fusion. (2004)
  • Author(s): Inagaki, H., et al.
  • Journal Title: Am J Surg Pathol. 28 (12) Pages: 1560-1567
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent celluar cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma (2004)
  • Author(s): Niwa, R., Hosaka, S. E., Sakurada, M., Shinkawa, T., Uchida, K., Nakamura, K., Matsushima, K., Ueda, R., Hanai, N, Shitara, K.
  • Journal Title: Cancer Res. 64(6) Pages: 2127-2133
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CXC chemokine receptor 3 and CC chemokine receptor 4 expression in T-cell and NK-cell lymphomas with special reference to clinicopathological significance for preripheral T-cell lymphoma, unspecified. (2004)
  • Author(s): Ishida, T., Inagaki, H., Utsunomiya, A., Takatsuka, Y., Komatsu, H., Iida, S., Takeuchi, G., Eimoto, T., Nakamura, S, Ueda, R.
  • Journal Title: Clin. Cancer Res. 10(16) Pages: 5494-5500
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Distribution of CXCR3- or CCR4-positive cells in interstitial pneumonia associated with primary Sjogren's syndrome. (2004)
  • Author(s): Shimizu, S., Yoshinouchi, T., Naniwa, T., Nakamura, M., Sato, S., Ohtsuki, Y, Fujita, J., Yamadori, I., Eimoto, T., Ueda, R.
  • Journal Title: Virchows Arch 445(5) Pages: 477-484
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma.. (2004)
  • Author(s): 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.
  • Journal Title: Clin. Cancer Res. 10(22) Pages: 7529-7539
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gastric MALT lymphomas are divided into three groups based on responsiveness to Helicobacter Pylori eradication and detection of API2-MALT1 fusion. ; (2004)
  • Author(s): Inagaki, H., Nakamura, T, Li C, Sugiyama, T., Asaka, M., Kodaira, J., Iwano, M., Chiba, T., Okazaki, K, Kato, A., Ueda, R., Eimoto, T., Okamoto, S., Sasaki, N., Uemura, N., Akamatsu, T., Miyabayashi, H., Kawamura, Y., Goto, H., Niwa, Y., Yokoi, T., Seto, M, Nakamura, S.
  • Journal Title: Am J Sure Pathol. 28(12) Pages: 1560-1567
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma. (2004)
  • Author(s): Ishida, T., Ueda, R.et al.
  • Journal Title: Clin.Cancer Res. 10 Pages: 7529-7539
• [Journal Article] CXCR3 and CCR4 expression in T-cell and NK-cell lymphomas with special reference to clinicopathological significance for preripheral T-cell lymphoma, Unspecified. (2004)
  • Author(s): Ishida, T., Ueda, R.et al.
  • Journal Title: Clin.Cancer Res. 10 Pages: 5494-5500
• [Journal Article] Defucosylated chimeric anti-CCR4 IgG1 with enhanced antiboy-dependent cellular cytotoxicity shows potent therapeutic anctiviy to T cell leukemia (2004)
  • Author(s): Niwa, R., Ueda, R.et al.
  • Journal Title: Cancer Res. 64 Pages: 2127-2133
• [Journal Article] Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. (2004)
  • Author(s): Ozeki, K., Ueda, R.et al.
  • Journal Title: Blood 103 Pages: 1901-1908
• [Journal Article] Familial essential Thrombocythemia associated with a dominant-positive Activating mutation of the c-MPL gene, which encodes for the receptor for Thrombopoietin. (2004)
  • Author(s): Ding, J., Ueda, R.et al.
  • Journal Title: Blood 103 Pages: 4198-4200
• [Journal Article] Clinical significance of a blood eosinophilia in adult T-cell leukemia/lymphoma : blood eosinophilia is a significant unfavorable prognostic factor
  • Author(s): Utsunomiya, A.
  • Journal Title: Leuk Res. (in press)
• [Journal Article] Differing distributions of CXCR3 - and CCR4 - positive cells among types of interstitial pneumonia associated with collagen vascular diseases.
  • Author(s): Shimizu, S.
  • Journal Title: Virchows Arch. (in press)
• [Book] 血液・腫瘍科 (2005)
  • Author(s): 石田 高司, 上田 龍三 他
  • Publisher: 科学評論社(出版予定)