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Development of immunotherapy targeting neoplastic lymphocyte-specific antigen (2D7) against hematological malignancies

Research Project

Project/Area Number 13557082
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Hematology
Research InstitutionThe University of Tokushima

Principal Investigator

MATSUMOTO Toshio  The University of Tokushima, Institute of Health Biosciences, Professor, 大学院・ヘルスバイオサイエンス研究部, 教授 (20157374)

Co-Investigator(Kenkyū-buntansha) ABE Masahiro  The University of Tokushima, University Hospital, Assistant Professor, 医学部・歯学部附属病院, 講師 (80263812)
OZAKI Shuji  The University of Tokushima, University Hospital, Assistant Professor, 医学部・歯学部附属病院, 講師 (90314872)
KAWAI Shigeto  Chugai Pharmaceutical Co.Ltd., Pharmaceutical Research 2, Researcher, 創薬第2研究所, 研究員
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥10,700,000 (Direct Cost: ¥10,700,000)
Fiscal Year 2003: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥4,300,000 (Direct Cost: ¥4,300,000)
Keywordshematoloeical malienanc / monoclonal antibody / immunotherary
Research Abstract

We first examined the expression of 2D7 antigen among hematological malignancies. Flow cytometric analysis showed. that 2D7 was highly expressed on myeloma cells and B-cell lymphoblastic cells. These cells expressed 2D7 at significantly higher levels than normal hematopoietic cells. Molecular cloning of 2D7 revealed that the epitope protein was a part of human histocompatibility leukocyte antigen (HLA) class I complex, HLA-A. We next investigated the biological function of 2D7 by using, 2D7 antibody. The 2D7 antibody induced cell death in neoplastic myeloma cells in the presence of secondary antibody in a dose-dependent manner. In contrast, 2D7 antibody did not affect cell viability of normal blood cells. To establish HLA class I-targeting therapy, we generated a recombinant single-chain Fv diabody (2D7 diabody). We found that 2D7 diabody induced myeloma cell death more efficiently than 2D7 antibody without any effector-mediated mechanisms. In a severe combined immunodeficiency mouse model of human myeloma, administration of 2D7 diabody significantly reduced M-protein level and prolonged survival of these mice. Next, we analyzed the mechanism of cell death induced by 2D7 diabody using several signal transduction inhibitors. 2D7 diabody-mediated cell death was completely inhibited by actin polymerization inhibitors such as cytochalasin D and latrunculin A, suggesting the involvement of actin network. In fact, 2D7 diabody induced actin aggregation and this type of cell death was different from classical apoptosis. These findings demonstrate that 2D7 diabody specifically and potently induces cell death of neoplastic lymphoid cells expressing high levels of HLA-A, and suggest that HLA-A is a potential target for immunotherapy in patients with lymphoid malignancies.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (23 results)

All 2004 2003 2002 Other

All Journal Article (12 results) Publications (11 results)

  • [Journal Article] Ability of myeloma cells to secrete macrophage inflammatory protein(MIP)-1a and MIP-1 b correlates with lytic bone lesions in patients with multiple myeloma2004

    • Author(s)
      Hashimoto T
    • Journal Title

      Br J Haematol 125

      Pages: 38-41

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Osteoclasts enhance myeloma cell growth and survival via cell-cell contact : a vicious cycle between bone destruction and myeloma expansion2004

    • Author(s)
      Abe M
    • Journal Title

      Blood 104

      Pages: 2484-2491

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] 2D7 diabody bound to the α2 domain of HLA class I efficiently induces caspase-independent cell death against malignant and activated lymphoid cells2004

    • Author(s)
      Kimura N
    • Journal Title

      Biochem Biophys Res Commun 325

      Pages: 1201-1209

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-la and MIP-1 b,correlates with lytic bone lesions in patients with multiple myeloma2004

    • Author(s)
      Hashimoto T, et al.
    • Journal Title

      Br J Haematol 125

      Pages: 38-41

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Osteoclasts enhance myeloma cell growth and survival via cell-cell contact : a vicious cycle between bone destruction and myeloma expansion2004

    • Author(s)
      Abe M, et al.
    • Journal Title

      Blood 104

      Pages: 2484-2491

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] 2D7 diabody bound to the alpha2 domain of HLA class I efficiently inducescaspase-independent cell death against malignant and activated lymphoid cells2004

    • Author(s)
      Kimura N, et al.
    • Journal Title

      Biochem Biophys Res Commun 325

      Pages: 1201-1209

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Expression of RANK is dependent upon differentiation into the macrophage/osteoclast lineage : induction by 1alpha, 25-dihydroxyvitamin D3 and TPA in a human myelomonocytic cell line, HL602003

    • Author(s)
      Kido S
    • Journal Title

      Bone 32

      Pages: 621-629

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Expression of RANK is dependent upon differentiation into the macrophage/osteoclast lineage: induction by 1 alpha, 2 5 -dihydroxyvitamin D3 and TPA in a human myelomonocytic cell line, HL602003

    • Author(s)
      Kido S, et al.
    • Journal Title

      Bone 32

      Pages: 621-629

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Role for macrophage inflammatory protein(MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma2002

    • Author(s)
      Abe M
    • Journal Title

      Blood 100

      Pages: 2195-2202

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts_by cognate interaction with activated T cells2002

    • Author(s)
      Abe M
    • Journal Title

      J Leukoc Biol 72

      Pages: 947-952

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Role for macrophage inflammatory protein (MIP)-lalpha and MIP-lbeta in the development of osteolytic lesions in multiple myeloma2002

    • Author(s)
      Abe M, et al.
    • Journal Title

      Blood 100

      Pages: 2195-2202

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts by cognate interaction with activated Tcells2002

    • Author(s)
      Abe M, et al.
    • Journal Title

      J Leukoc Biol 72

      Pages: 947-952

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Abe M: "Interleukin-1 beta enhances and interferon-gamma suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts"Clin Exp Immunol. 126巻1号. 64-68 (2001)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hashimoto T: "Superantigens and autoantigens may be involved in the pathogenesis of gastric mucosa-associated lymphoid tissue lymphoma"Int J Hematol. 74巻2号. 197-204 (2001)

    • Related Report
      2003 Annual Research Report
  • [Publications] Abe M: "Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma"Blood. 100巻6号. 2195-2202 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Abe M: "Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts by cognate interaction with activated T cells"J Leukoc Biol. 72巻2号. 947-952 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsumoto T: "Comparative study of incadronate and elcatonin in patients with malignancy-associated hypercalcaemia"J Int Med Res. 30巻3号. 230-243 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hashimoto T: "Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1a and MIP-1 b correlates with lytic bone lesions in patients with multiple myeloma"Br J Haematol. 125巻1号. 38-41 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Abe M: "Interleukin-1 beta enhances and interferon-gamma suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts"Clin Exp Immunol. 126巻1号. 64-68 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hashimoto T: "Superantigens and autoantigens may be involved in the pathogenesis of gastric mucosa-associated lymphoid tissue lymphoma"Int J Hematol. 74巻2号. 197-204 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Abe M: "Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma"Blood. 100巻6号. 2195-2202 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Abe M: "Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts by cognate interaction with activated T cells"J Leukoc Biol. 72巻2号. 947-952 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsumoto T: "Comparative study of incadronate and elcatonin in patients with malignancy-associated hypercalcaemia"J Int Med Res. 30巻3号. 230-243 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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