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Molecular targeting against growth factor receptors by a novel drug compord of human fusion proteins

Research Project

Project/Area Number 09470258
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionKeio University

Principal Investigator

UEDA Masakazu  Keio Univ., Surgery, Assistant Professor, 医学部, 講師 (50142419)

Co-Investigator(Kenkyū-buntansha) KAMEYAMA Noriaki  Keio Univ., Surgery, Assistant, 医学部, 助手 (50276268)
WATANABE Yasuo  Keio Univ., Surgery, Assistant, 医学部, 助手 (20265846)
OZAWA Soji  Keio Univ., Surgery, Assistant Professor, 医学部, 講師 (10169287)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 1999: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1998: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1997: ¥7,600,000 (Direct Cost: ¥7,600,000)
KeywordsMissils therapy / growth factor / growth factor receplor / IL-2 / EGF / IL-2 receptor / fusion protein / ActinomycinD / 抗癌剤 / 免疫抑制剤 / 増殖因子受容体 / RNase / EGF受容体 / EGF / IL-2受容体 / IL-2 / EGF-RNase / リコンビナントタンパク / 抗炎症剤
Research Abstract

To develop a new Missile therapy targeted at growth factor receptor, fusion proteins with a human Rnase and monoclonal antibody against growth factor receptors or growth factor. A hybrid human protein was engineered by fusing the genes encoding human pancreatic Rnase 1 and human IL-2, was isolated and refolded from E.coli inclusion bodies, and was purified to homogeneity. The hpRNase1-hIL-2 inhibited protein synthesis in HTLV-1 infected, malignant T lymphocytes, hyperproducing high affinity IL-2 receptors, with an IC50 of 2x10-8M, whereas no inhibition was detectable for receptor deficient control cells or hpRNase 1 alone had an IL50 of almost 10-3M.. A molar excess of hIL-2 locked the protein synthesis inhibition dose dependently. In a human mixed lymphocyte culture, hpRNase 1-hIL-2 inhibited the proliferation of responder cells with potency comparable to that of cyclosporine, while minimal doses of FK506 importantly improved its potency. Concentrations comparable to the IC50 in vitro could be safely achieved in animals, and could be escalated without any toxic side effects. The murine monoclonal antibody (528) against the human epidermal growth factor receptor (EGFR) was conjugated with mammalian pancreatic Rnase via SPDP and 2-IT. The conjugate showed dose-dependent cytotoxicity against EGFR-producing squamous cancer cells and no detectable cytotoxicity against EGFR-deficient small cell lung cancer cells. The cytotoxicity of the conjugate was positively correlated with the EGFR numbers of each cell line. The addition of excess 528 antibody to the medium rotected A431 cells from the conjugate cytotoxicity. This immunoconjugate might be useful for targeted treatment of squamous cell carcinomas hyperexpressing EGFR.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Psarras K.: "Targeting activated lymphocytes with an entirely human immunotoxin analog: Human pancreatci RNase1-human IL-2 fusion"Cytokine. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Suwa T.: "Epidermal growth factor receptor-dependent cytotoxic effect of anti-EGFR antibody-ribonuclease conjugate o human cancer cell"Anticancer Res.. 19. 4161-4166 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Futami J.: "Inhibition of cell growth by a fused protein of human ribonuclease 1 and human fibroblast growth factor"Protein Engineering. 12. 1013-1019 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Psarras K: "Human Pancreatic RNase1-human EGF fusion: an entirely human immunotoxin analogy with cytotoxic properties against squamous cell rowth"Protein ENgineering. 11. 1285-1292 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kaneta Y: "Effect of gelonin immunoconjugate with monoclenal antibody MSN-1 to extometrial adenocarcinoma on antigen-producing-lumor cells in vivo"Jpn. J. Cancer Res.. 89. 583-588 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Suwa T.: "Magnetic resonance imaging of esophageal squamous cell carcinoma using magnotite particles coated with anti-EGF antibody"Int J. Cancer. 75. 626-634 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shin C. et al.: "Vascular endothelial qrowth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophaqus"Clin. Cancer Res. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Psarras K. et al: "Tarteting IL-2 receptors with an entirely human immunotoxin analog: human pancreatic Rnase-human IL-2 fuion"Cvtokine. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Futami. J. et al: "Inhibition of cell qrowth by a fuxed of human ribonucleasel and human fibroblast qrowth factor"Protein Eng. 12. 1013-1019 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Suwa T. et al: "Epidermal qrowth factor receptor-dependent cytotoxic effect of anti-EGFR antibbody-ribonuclease conjugate on human cancer cells"Anticancer Res. 19. 4169-4166 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Koyanagi K. et al: "Clinical singnificance of telomerase acitivity in non-cancerous epitelial region of the esophaqeal cancer"Br. J. Surgery. 86. 674-679 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Psarras K. et al.: "Human pancreatic Rnase 1- human epidermal growth factor fusion: an enntirely human immunotoxin analog with cytotoxic properities against sguamous cell carcinoma"Protein Eng. 11. 1285-1292 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kaneta Y. et al: "Effects of gelonin immunotoxin conjugate with monoclonal antibody MSN-1 to endometrial edenocarcinomas on antigen-producing tumors cells in vivo"Jpn. J. Cancer Res. 89. 583-588 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Suwa T. et al: "Magnetic resonance imaging of esophageal sguamous cell carcinoma using magnetite particles coated with anti-epidermal growth factor receptor antibody"Int. J. Cancer. 75. 626-634 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ueda M.. Et al.: "Molecular tarteting for epidermal growth factor receptor expressed on cancer cells by human fusion protien"Breast Cancer. 4. 253-255 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Psarras K,,et al.: "Targeting activated lymphocytes with an entirely human immunotoxin analog"Cytokine. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Suwa T.,et al.: "Epidermal growth factor receptor-dependent cytotoxic effect of anti-EGFR antibody-ribonuclease conjngate on human concer cells"Anticancer Res.. 19. 4161-4166 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Futami J.,et al: "Inhibition of cell growth by a fused protein of human ribonuclease 1 and human basic fibroblast growth factor"Protein Engineering. 12. 1013-1019 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yasumori T.,et al: "Human CYP2C-mediated stereo selective phenytoin hydroxylation in Japanese:Difference in Chiral preference of CYP2 C9 and CYP2 C19"Biochemical Pharmacology. 57. 1297-1303 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Koyanagi K: "Clinical Significance of Telomerase Activity in the Noncancerous Epithelial Region of Oesophageal Squdmous Cell Carcinoma" British J Surgery. (in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] Psarras K: "Human pancreatic RNase1-human EGF fusion: an entirely human immuni toxin anilog' with cytotoxic properties against squamous cell carcinoma" Protein Engineering. 11(12). 1285-1292 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Futami J: "Inhibition of cell growth by a fused protein of human RNase1 and human bFGF" Growth Factors. (in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] Kaneta Y: "Effect of gelonin immunoconjugate with monoclonal antibody MSN-1 to endometrial alenocarcinoma on antigen-producing tumor cells in vivo" Jpn.J.Cancer Res.89. 583-588 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shito M: "Pathophysiological to response of cytokines and vasoactive agents in patients undergoing total gastretomy" Eur J Surg. 164. 115-118 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Suwa T: "Magnetic resorance imaging of asophageal squamouns cell carcinoma using magnetite particles coatel with anti-EGF antibody" Int.J.Cancer. 75. 626-634 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Suwa: "MRI of esophageal squamous cell carcinoma using magnetic particles coated with anti-EGF receptor antibody." Int.J.Cancer. 75. 626-634 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Ueda: "Molecular targeting for EGF receptor expressed on breast cancer cells by human fusion protein." Breast Cancer. 4. 253-255 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Kaneta: "Effects of gelonin conjugate with monoclonal antibody MSN-1 and endometrial adenocarcinoma in vitro." Oncology Report. 4. 331-336 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] T.Takeuchi: "Altered p16/MTS1/COKN2 and cyclinD1/pRAD-1 gene expression is associated with prognasis of squamous cell carcinoma of the esophagus." Clin.Cancer Res.3. 2229-2236 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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