抗体療法及びがんの前臨床試験研究

• Project/Area Number: 12217127
• 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: 上田 龍三 名古屋市立大学, 大学院・医学研究科, 教授 (20142169)
• Co-Investigator(Kenkyū-buntansha): 佐藤 滋樹 名古屋市立大学, 大学院・医学研究科, 助教授 (80254283) ; 折戸 悦郎 名古屋市立大学, 大学院・医学研究科, 講師 (60204294) ; 吉川 和宏 (吉川 和弘) 愛知医科大学, 医学部, 講師 (60109759) ; 直江 知樹 名古屋大学, 医学部, 助教授 (50217634)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥148,600,000 (Direct Cost: ¥148,600,000); Fiscal Year 2004: ¥29,200,000 (Direct Cost: ¥29,200,000); Fiscal Year 2003: ¥29,300,000 (Direct Cost: ¥29,300,000); Fiscal Year 2002: ¥30,000,000 (Direct Cost: ¥30,000,000); Fiscal Year 2001: ¥28,100,000 (Direct Cost: ¥28,100,000); Fiscal Year 2000: ¥32,000,000 (Direct Cost: ¥32,000,000)
• Keywords: 抗体療法 / 前臨床試験 / 分子標的療法 / ガングリオシド / 抗体リモデリング / 肝炎ウイルス / ケモカイン / MUM1 / 抗体 / translation research / ハイリスクgenotype / ガングリオシドGD2抗体 / IRF4 / 抗変異EGFレセプター抗体(3C10) / ヒト化抗体 / ケモカインCCR4 / リモデリング / 抗ガングリオシド抗体 / FLT3遺伝子 / 抗ケモカインレセプター抗体 / ウィルス発癌 / 抗c-kit / CEA / CD25抗体 / ガングリオシドGD2 / ヒストンデアセチラーゼ(HDAC) / FK228

Research Abstract

新たながんの診断と治療法開発に向けて、抗体技術を用いての前臨床試験をにらんで分子基盤に基づいた研究を推進した。B型肝炎による肝癌発症に関わる研究では、HBe抗原はPreC領域の変異と関連し、core promoter領域変異との病態の進展やgenotypeとの関連性を明らかにした。また、若年者肝癌発症のリスクに関わるHBVの組み換え配列を同定し、その血清診断への応用の基礎を築いた。肺小細胞癌においてガングリオシドGD2蛋白発現は癌細胞の増殖や浸潤性に関与し、抗GD2抗体はJNK/SAPKの活性化を介したカスペース活性依存性アポトーシスの誘導により抗腫瘍効果を発揮することを見出した。リンパ系腫瘍発症に関わる転写制御因子MUM1に関してはその下流分子としてケモカインであるMIG分子を見つけ、B細胞性慢性リンパ性白血病(B-CLL)細胞のうち50%がMIGを発現し、抗MIGあるいは抗CXCR3中和抗体を用いて腫瘍増殖抑制効果を見出し、あらたなリンパ系腫瘍における分子標的を同定した。抗体リモデリングでは、抗変異EGFレセプター抗体の単鎖抗体の作製に成功し、99mTc標識となり可能となり、脳内移植腫瘍に対し極めて高い集積性を確認し得た。また、細胞増殖に関わるp16inkの最小機能ドメインをp16ink欠損腫瘍細胞に導入し、明らかな細胞増殖阻害を確認、抗体分子の生細胞内での機能化に成功し、トランスポーターペプタイドの開発を推進した。ケモカインを標的とした抗体療法の開発では、成人T細胞性白血病を始めとしたT細胞性腫瘍においてCCR4分子が高頻度に発現し、独立した予後因子であるとともに腫瘍生物学的重要性に深く関わること、さらには低フコース化したCCR4抗体による強力な抗腫瘍効果をin vitroおよびin vivoで明らかにでき、早期臨床試験の基盤的研究を完遂する事ができた。

Research Products

• [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] Defucosylated chimeric anti-CCR4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T cell leukemia and lymphoma. (2004)
  • Author(s): Niwa, R., Ueda, R.et al.
  • Journal Title: Cancer Res. 64 Pages: 2127-2133
• [Journal Article] Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C. (2003)
  • Author(s): Orito, E., Ueda, R.et al.
  • Journal Title: Gastroenterology. 124 Pages: 925-932
• [Journal Article] Hepatitis B e antigen in sera from individuals infected with hepatitis B virus of genotype G. (2002)
  • Author(s): Orito, E., Ueda, R.et al.
  • Journal Title: Hepatology. 35 Pages: 922-929
• [Journal Article] Ganglioside G(D2) in small cell lung cancer cell lines : enhancement of cell proliferation and mediation of apoptosis. (2001)
  • Author(s): Yoshida, S., Ueda, R.et al.
  • Journal Title: Cancer Res. 61 Pages: 4244-4252
• [Journal Article] Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis-A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. (2000)
  • Author(s): Kondo, Y., Ueda, R.et al.
  • Journal Title: Hepatology. 32 Pages: 970-979
• [Book] 成人T細胞性白血病/リンパ腫における新規標的分子としてのケモカインレセプター:CCR4.XI腫瘍免疫、移植免疫.Annual Review 免疫 2005(編集:奥村康、平野俊夫、佐藤昇志) (2005)
  • Author(s): 石田高司, 上田龍三, 設楽研也
  • Publisher: 中外医学社
• [Publications] Niwa, R, Ueda, R. et al.: "Defucosylated chimeric anti-CCR4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent thrapeutic activity to T cell leukemia and lymphoma."Cancer Res. (in press).
• [Publications] Ozeki, K., Ueda., R.et al.: "Biological and clinical significance of the FLT3 transcript level in acute myeloid leukemia"Blood. (in press).
• [Publications] Ding, J., Iida, S., Ueda, R.et al.: "Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin."Blood. (in press).
• [Publications] Ishida, T., Iida S., Ueda, R.et al.: "Clinical significance of CCR4 expression in adult T-cell leukemia/lynphoma (ATLL):its close association with skin involvement and unfavorable outcome."Clin Cancer Res.. 9. 3625-3634 (2003)
• [Publications] Sugauchi, F., Ueda, R.et al.: "Epidemiological and virological characteristics of hepatitis B virus genotype B having the recombination with genotype C."Gastroenterology. 124. 925-932 (2003)
• [Publications] Minami, Y., Ueda, R.et al.: "Different antiapoptotic pathways between wild-type and mutated FLT3 : insights into therapeutic targets in leukemia."Blood. 102. 2969-2975 (2003)
• [Publications] Okabe, M., Ueda, R.et al.: "API2-MALT1 fusion defines a distinctive clinicopathologic subtype in pulmonary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue"Am.J.Pathology. 162(4). 1113-1122 (2003)
• [Publications] Ueda, R.: "Multistep tumorigenesis of multiple myeloma : its molecular delineation."Int.J.Hematology. 77. 207-212 (2003)
• [Publications] Miura, K., Ueda, R.et al.: "Frequent occurrence of CCND1 deregulation in patients with early stages of plasma cell dyscrasia."Cancer Science. 94(4). 350-354 (2003)
• [Publications] Ito, H., Sato, S., Ueda, R.et al.: "A limited association of OGG1 ser326Cys polymorphism for adenocarcinoma of the lung."J.Epidemiology. 12(3). 258-265 (2003)
• [Publications] Kato, H., Orito, E., Ueda, R., et al.: "Regression of esophageal papillomatous polyposis caused by high-risk type human papilloma virus."J.Gastroenterol. 38. 579-583 (2003)
• [Publications] Miyazaki, H., Sato, S., Ueda, R.et al.: "Potential limitations in using minor histocompatibility antigen-specific cytotoxic T cells for targeting solid tumor cells."Clinical Immunology. 107. 198-201 (2003)
• [Publications] Achiwa, H., Sato, S., Ueda, R.et al.: "Analysis of βtubulin gene alteration in human lung cancer cell lines."Cancer letters. 201. 211-216 (2003)
• [Publications] Yamaguchi, M.: "De novo CD5^+ positive diffuse large B-cell lymphoma a clinicopathologic study of 109 patients"Blood. 99. 815-821 (2002)
• [Publications] Naoe, T.: "Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia increased early death after chemotherapy"Leukemia. 16. 203-208 (2002)
• [Publications] Inagaki, H.: "Primary thymic extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue type exhibits Distinctive clinicopathological and molecular features"Am. J. Pathology. 160・4. 1435-1443 (2002)
• [Publications] Sanda, T.: "Successful treatment of nasal T-cell lymphoma with combination of local irradiation and high-dose chemotherapy"Int. J. Hematology. 75. 195-200 (2002)
• [Publications] Kato, H.: "Hepatitis Be antigen in sera from individuals infected with hepatitis B virus of genotype G"Hepatology. 35・4. 922-929 (2002)
• [Publications] Kiyoki, H.: "Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain"Oncogene. 21. 2555-2563 (2002)
• [Publications] Sugauchi, F.: "Hepatitis B virus of genotype B with or without recombination with genotype C over the precore region plus the Core Gene"J. Virol.. 76・12. 5985-5992 (2002)
• [Publications] Ito, M.: "MUM1/IRF4 expression is an unfavorable prognostic factor in B-cell chronic lymphocytic leukemia(CLL)/small lymahocytic lymphoma(SLL)"Jpn. J. Cancer Res.. 93. 685-694 (2002)
• [Publications] Yoshida, S.: "An anti-GD2 monoclonal antibody enhances apoptotic effects of anti-cancer drugs against small cell lung cancer cells via JNK(c-Jun Terminal Kinase) activation"Jpn. J. Cancer Res.. 93. 816-824 (2002)
• [Publications] Minami, Y.: "Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cell by Hsp90 inhibitors"Leukemia. 16. 1535-1540 (2002)
• [Publications] Sugauchi, F.: "Genotype, Serotype, and Phylogenetic characterization of the complete genome sequence of hepatitis B virus isolates from Malawian chronic carriers of the virus"J. Medical Virology. 69. 33-40 (2003)
• [Publications] Nomura, K.: "Detection of t(11;18)(q21;q21) in marginal zone lymphoma of mucosa-associated lymphocytic tissue type on paraffin-embedded tissue sections by using fluorescence in situ hybridization"Cancer Genetics and Cytogenetics. 140. 49-54 (2003)
• [Publications] Luo, J.M.: "Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia"Leukemia. 17. 1-8 (2003)
• [Publications] Iida, S.: "Multistep tumorigenesis of multiple myeloma : its molecular delineation"Int. J. Hematology. (in press). (2003)
• [Publications] Hanamura, I.: "Ectopic expression of MAFB gene in human myeloma cells carrying(14;20)(q32;q11)chromosomal translocations"Jpn.J.Cancer Res.. 92. 638-644 (2001)
• [Publications] Yamamoto, Y.: "Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies"Blood. 97・8. 2434-2439 (2001)
• [Publications] Inagaki, H.: "API2-MALT1 fusion transcripts involved in mucosa-associated lymphoid tissue lymphoma"Am.J.Pathology. 158・2. 699-709 (2001)
• [Publications] Kosugi, H.: "In vivo effects of a histone deacetylase inhibitor,FK228,on human acute promyelocytic leukemia in NOD/Shi-scid/scid Mice"Jpn.J.Cancer Res.. 92. 529-536 (2001)
• [Publications] Inagaki, H.: "Clonality assay of hematopoietic disorders:significance of the buccal epithelium as non-hematopoietic control and of 95% rejection limit as a novel criterion for monoclonality"Jpn.J.Cancer Res.. 92. 1305-1312 (2001)
• [Publications] Kato, M.: "Pregnancy-associated cytotoxic lymphoma:a repor of four cases"Int.J.Haematol.. 74. 186-192 (2001)
• [Publications] Eguchi, M.: "GPHN,a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24):Genes"Chromosomes & Cancer. 32. 212-221 (2001)
• [Publications] Yamaguchi, M.: "De novo CD5+ positive diffuse large B-cell lymphoma:a clinicopathologic study of 109 patients"Blood. 99. 815-821 (2001)
• [Publications] Ogisu, N.: "Elevated level of soluble HLA class I antigens in serum and bronchoalveolar lavage fluid in patients with sarcoidosis"Int.Medicine. 40・3. 201-207 (2001)
• [Publications] Yoshida, S.: "Ganglioside GD2 in small cell lung cancer cell lines:enhancement of cell proliferation and mediation of apoptosis"Cancer Res.. 61. 4244-4252 (2001)
• [Publications] Sugauchi, F.: "A novel variant genotype C of hepatitis B virus identified in isolates from Australian aborigines:complete genome sequence and phylogenetic relatedness"J.General Virology. 82. 883-892 (2001)
• [Publications] Fujita, J.: "Non-specific interstitial pneumonia as pulmonary involvement of systemic sclerosis"Annals of the Rheumatic Diseases. 60・3. 281-283 (2001)
• [Publications] Kato, H.: "Determination of hepatitis B virus genotype G by polymerase chain reaction with hemi-nested primers"J.Virological Methods. 98. 153-159 (2001)
• [Publications] Ding, X.: "Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai,China"Intervirology. 44. 43-47 (2001)
• [Publications] Ruzibakiev, R.: "Risk factors and seroprevalence of hepatitis B virus,hepatitis C virus,and human immunodeficiency virus infection in Uzbekistan"Intervirology. 44. 327-332 (2001)
• [Publications] Tsuboi, K.: "Lymphoid blastic crisis of chronic myelogenous leukemia with inv(16)(p13;q22)"Leukemia Res.. (in press).
• [Publications] Naoe, T.: "Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia:increased early death after chemotherap"Leukemia. 16. 203-208 (2002)
• [Publications] Kato, H.: "Hepatitis B e antigen in sera from individuals infected with hepatitis B virus of genotype G"Hepatology. (in press).
• [Publications] Tsuboi,K.: "MUM1/IRF4 expression as a frequent event in mature lymphoid Malignancies "Leukemia. 14. 449-456 (2000)
• [Publications] Takeyama,K.: "Therapy-related leukemia and myelodysplastic syndrome : a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors"Int.J.Hematol.,. 71. 144-152 (2000)
• [Publications] Zhao,M.: "In vivo treatment of mutant FLT3-transformed munne leukemia with a tyrosine kinase inhibitor."Leukemia. 14. 374-378 (2000)
• [Publications] Naoe,T.: "Analysis of genetic polymoriphism in NQO1,GST-M1,GST-T1,and CYP3A4 in 469 Japanese patients with therapy-related leukemia/myelodysplasic syndrome and de novo acute myeloid leukemia."Clin.Cancer Res.. 6. 4091-4095 (2000)
• [Publications] Murata,M.: "Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228,on malignant lymphoid cells"Jpn.J.Cancer Res.. 91. 1154-1160 (2000)
• [Publications] Kitamura,K.: "Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis"Leukemia. 14・10. 1743-1750 (2000)
• [Publications] Kitamura,K.: "Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid"Br J Haematol.. 108・4. 696-702 (2000)
• [Publications] Hayakawa,F.: "Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lin"Oncogene. 19・5. 624-631 (2000)
• [Publications] Kitagawa,N.: "Epstein-Barr virus-encoded poly(A)(-) RNA supports lymphoma growth through interleukin-10 induction. "EMBO J.. 19・24. 6742-6750 (2000)
• [Publications] Shimizu,S.: "High frequency of clonally related tumors in cases of multiple synchronous lung canceres as revealed by molecular diagnosis"Clin.Cancer Res.. 6. 3994-3999 (2000)
• [Publications] Hayashi,K.: "Usefulness of uracil loading test for detecting 5-flurorouracil metabolic enzyme deficiencies in humans"Int.J.Clin.Oncol.. 5. 171-173 (2000)
• [Publications] Niimi,T.: "Vitamin D receptor gene polymorphism and calcium metabolism in sarcoidosis patients."Basic Science Res.. 17. 266-269 (2000)
• [Publications] Maeda,H.: "Human herpesvirus 8 is not associated with sarcoidosis in Japanese Patients"Chest. 118. 923-927 (2000)
• [Publications] Takeshita,A.: "Quantitative expression of erythropoietin receptor (EPO-R) on acute leukemia cells : relationships between the amount of EPO-R and CD phenotypes, in vitro proliferative response,the amount of other cytokine receptors and clinical prognosis"Brit.J.Hematology. 108. 55-63 (2000)
• [Publications] Tanaka,H: "Lack of integrated TT virus (TTV) genomes into cellular DNA in infected human hematopoietic cells"Leukemia and Lymphoma. 38. 411-417 (2000)
• [Publications] Iida,S.: "Anobel human multiple myeloma-derived cell line, NCU-MM-1,carrying(2;11)(Pll;q23) and (8;22)(q24;qll)chromosomal translocations with overexpression of c-myc protein"Int.J.Hematol.. 72. 85-97 (2000)