Studies of antibody therapy for treatment of adult T-cell leukemia targeting surface carbohydrate molecules

2009 Fiscal Year Final Research Report

• Project/Area Number: 19390153
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kagoshima University
• Principal Investigator: BABA Masanori Kagoshima University, 大学院・医歯学総合研究科, 教授 (70181039)
• Co-Investigator(Kenkyū-buntansha): ARIMA Naomichi 鹿児島大学, 大学院・医歯学総合研究科, 教授 (30175997) ; SUDA Yasuo 鹿児島大学, 大学院・理工学研究科, 教授 (70179282) ; ITOU Yuji 鹿児島大学, 大学院・医歯学総合研究科, 准教授 (60223195)
• Project Period (FY): 2007 – 2009
• Keywords: HTLV-1 / ATL / 表面分子 / 糖鎖 / 抗体分子

Research Abstract

Comprehensive analysis for the gene expression of human T-cell leukemia virus type 1 (HTLV-1)-infected and uninfected T cell lines by DNA microarray revealed that CD70 was a molecule highly and specifically expressed on the surface of adult T-cell leukemia (ATL) cells. Further analysis for the gene expression of glycosyltransferases by real-time PCR and high-throughput analysis of cell surface sugar chains by mass spectrometry demonstrated the existence of several ATL cell-specific sugar chains. In addition, with a newly developed fluorescent linker compound, the surface sugar chains of ATL cells were successfully immobilized on a chip. Using a human single chain Fv (scFv) phage library, a scFv specific to an ATL cell line was successfully isolated. The antigen recognized by the scFv was HLA-DR1β, which was also highly expressed on the surface of ATL cells. The scFv could induce the apoptosis of the ATL cell line at low concentrations in its dimer form. To obtain the scFv that binds to ATL cell-specific surface sugar antigens, a novel synthetic scFv library was constructed by introducing random mutations on the complementary determining regions (CDR) of a single frame antibody.

Research Products

• [Journal Article] Discovery of hydrotetramethylnaphthalene analogs as adult T-cell leukemia cell-selective proliferation inhibitors in a small chemical library constructed based on multi-template hyposhesis. (2009)
  • Author(s): Nakamura M, Hamasaki T, Tokitou M, Baba M, Hashimoto Y, Aoyama H
  • Journal Title: Bioorg. Med. Chem 17 Pages: 4740-4746
  • Peer Reviewed
• [Journal Article] High sensitivity analysis of N NH S S O H2N naturally occurring sugar chains, using a novel fluorescent linker molecule. (2009)
  • Author(s): Sato M, Ito Y, Arima N, Baba M, Sobel M, Wakao M, Suda Y
  • Journal Title: J. Biochemistry 146 Pages: 22-41
  • Peer Reviewed
• [Journal Article] Effective induction of cell death on adult T-cell leukemia cells by HLA-DRβ-specific small antibody fragment isolated from human antibody phage library. (2009)
  • Author(s): uraoka S, Ito Y, Kamimura M, Baba M, Arima N, Suda Y, Hashiguchi S, Torikai M, Nakashima T, Sugimura K
  • Journal Title: J. Biochemistry 145 Pages: 799-810
  • Peer Reviewed
• [Journal Article] Highly enhanced expression of CD70 on human T-lymphotropic virus type 1-carrying cell lines and adult T-cell leulemia cells. (2008)
  • Author(s): Baba M, Okamoto M, Hamasaki T, Horai S, Wang X, Ito Y, Suda Y, Arima N
  • Journal Title: J. Virol 82 Pages: 3843-3852
  • Peer Reviewed
• [Presentation] 抗ATL活性を有する新規薬剤の探索とその作用機序解析 (2009)
  • Author(s): 外山政明, 濱崎隆之, 馬場昌範
  • Organizer: 第57回日本ウイルス学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2009-10-26
• [Presentation] 抗体ファージライブラリから得られたHLA-DR特異的な低分子抗体によるHTLV-1感染細胞への効果的な細胞死誘導 (2009)
  • Author(s): 伊東祐二, 杉村和久, 鳥飼正治, 中島敏博, 隅田泰生, 有馬直道, 馬場昌範
  • Organizer: 第2回HTLV-1研究会・合同班会議
  • Place of Presentation: 東京
  • Year and Date: 2009-08-30
• [Presentation] 成人T細胞白血病細胞株S1Tに特異的に発現する糖鎖の解析 (2008)
  • Author(s): 佐藤昌紀, 時任真衣子, 濱崎隆之, 馬場昌範, 有馬直道, 伊東祐二, 伊藤浩美, 澤木弘道, 成松久, 若尾雅広, 隅田泰生
  • Organizer: BMB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-10
• [Presentation] Improvement of human antibody fragment to enhance apoptosis-inducing activity against HTLV-1 infected T cells (2008)
  • Author(s): Muraoka S, Ito Y, Kamimura M, Baba M, Torikai M, Nakashima T, Hashiguchi S, Sugimura K
  • Organizer: 第38回日本免疫学会総会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-02
• [Presentation] ATL細胞特異的に抗腫瘍効果を有する薬剤の探索 (2008)
  • Author(s): 時任真衣子, 濱崎隆之, 馬場昌範
  • Organizer: 第56回日本ウイルス学会学術集会
  • Place of Presentation: 岡山
  • Year and Date: 2008-10-27
• [Presentation] 成人t細胞白血病細胞表層に特異的に発現する糖鎖解析 (2008)
  • Author(s): 佐藤昌紀, 時任麻衣子, 濱崎隆之, 馬場昌範, 有馬直道, 伊東祐二, 伊藤浩美, 澤木弘道, 成松久, 若尾雅広, 隅田泰生
  • Organizer: 第28回日本糖質学会年会
  • Place of Presentation: つくば
  • Year and Date: 2008-08-18
• [Presentation] Identification of surface molecules overexpressed on HTLV-1-carrying cells as potential target s of monoclonal antibodies for inhibition of adult T-cell leukemia (ATL) (2007)
  • Author(s): Baba M, Okamoto M, Hamasaki T, Muraoka S, Horai S, Wang X, Suda Y, Ito Y, Arima N
  • Organizer: Joint Seminar under the Japan-Korea Basic Scientific Cooperation Program "Novel Approach to Antiviral Chemotherapy and Its Practical Application"
  • Place of Presentation: Cheju, Korea
  • Year and Date: 2007-12-06
• [Presentation] Human single chain antibody specific to ATL-derived leukemic clone cells by biopanning from human antibody phage library can effectively induce apoptosis-like cell death (2007)
  • Author(s): Muraoka S, Ito Y, Baba M, Arima N, Suda Y, Nakashima T, Torikai M, Hashiguchi S, Sugimura K
  • Organizer: IBC's 18th Annual International Conference "Antibody Engineering"
  • Place of Presentation: San Diego, USA
  • Year and Date: 2007-12-03
• [Presentation] Targeting surface molecules overexpressed on HTLV-1-carrying cells as potential approach to anti-adult T-cell leukemia therapy (2007)
  • Author(s): Baba M
  • Organizer: 3rd Symposium of High Technology Research Center
  • Place of Presentation: Narashino, Japan
  • Year and Date: 2007-11-16
• [Patent(Industrial Property Rights)] 成人T細胞白血病治療薬 (2009)
  • Inventor(s): 馬場昌範, 橋本祐一
  • Industrial Property Rights Holder: 鹿児島大学
  • Industrial Property Number: 特願・2009-068750
  • Filing Date: 2009-03-19
• [Patent(Industrial Property Rights)] 多岐用途型蛍光性リンカー化合物、及びその製造方法ならびにそれらを用いて製造するリガンド複合体 (2008)
  • Inventor(s): 隅田泰生, 若尾雅広, 佐藤昌紀, 馬場昌範, 有馬直道, 伊東祐二
  • Industrial Property Rights Holder: (株)スディックスバイオテック,鹿児島大学
  • Industrial Property Number: 特願・2008-108561
  • Filing Date: 2008-04-18
• [Patent(Industrial Property Rights)] アポトーシス誘導能を有するヒト抗体 (2007)
  • Inventor(s): 伊東祐二, 馬場昌範, 有馬直道, 隅田泰生, 中島敏博, 鳥飼正治
  • Industrial Property Rights Holder: 鹿児島大学,財団法人化学及血清療法研究所
  • Industrial Property Number: 特願・2007-299551
  • Filing Date: 2007-11-19