Anti-cancer therapy for gastrointestinal canser using cytotoxic T cells and bispecific antibody
| Project/Area Number | 07671359 |
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Yamagata university School of medicine |
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Principal Investigator |
USUBA Osamu Yamagata university School of medicine, Surgery, assistant professor, 医学部, 講師 (60185014)
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| Co-Investigator(Kenkyū-buntansha) |
KIMURA Seishi Yamagata university School of medicine, Surgery, assistant professor, 医学部, 助手 (10234361)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed(Fiscal Year 1997)
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| Budget Amount *help |
¥2,400,000 (Direct Cost : ¥2,400,000)
Fiscal Year 1997 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1996 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1995 : ¥700,000 (Direct Cost : ¥700,000)
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| Keywords | Bispecific antibody / Cytotoxic T lymphocytes / Gastrointestinal canser therapy / Hybridhybridoma / HPLC / anti-CD3 antibody / Fc receptor / bispecitic / MAb(モノクローナル抗体) / 培養因子 / CTL(細胞障害性T細胞) / bispecific / MAb(モノクローナール抗体) / 接着因子 / bispcific / MAb / 細胞障害性T細胞 |
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| Research Abstract |
Cytotoxic T lymphocytes can lyse Fc receptor-bearing target cells in vitro in the presence of anti-CD3 antibodies. This "redirected" lysis is not restricted by major histocompatibility antigen nor does it require nominal antigen recognition by the CTL.The efficacy of redirected lysis in vivo was assessed by comparing the survival of mice inoculated with a melanoma cell line transfected with the gene for mouse Fc receptor versus the untransfected melanoma when inoculated with syngenic mouse CTL and anti-CD3 antibody. Survival was significantly higher in the animals given injections of Fc receptor positive melanoma, CTL,and anti-CD3 monoclonal antibody. Redirected lysis does not preclude the establishment of tumor immunity, since animals that rejected the tumor as a result of redirected lysis exhibited an increased resistance to reinoculation with tumor cells.
Studies over the last several years have demonstrated that antibodies to the TCR or CD3 can activate cells in the absence of Ag an
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d MHC gene products. An alter native approach to harnessing the cytotoxic potential of CTL can be to use bispecific antibodies to direct and activate CTL of various specificities to lyse cells expressing virus or tumor Ag. Bispecific antibodies with specificity for the TCR/CD3 complex as well as to a target cell-surface Ag can redirect CTL to lyse the target cell. We have produced a hybridhybridoma, HHA6, which secretes bispecific antibodies capable of redirecting CTL to lyse influenza virus-infected target cells. When added along with CTL to virus-infected cells, these antibodies very efficientlyenhace cytotoxic abilities of CTL.Because hybridhybridomas reassort H and L chains randomly we attempted to purify bispecific antibody by using HPLC.The purification increased the potency of HHA6. This increase and removal of inhibiting antibody species. From these experimental results, we have attempted to produce human hybridhybridoma which secretes bispecific antibodies capable of redircting human CTL to lyse human tumor cells.
Because of unstableness of human hybridhybridoma, we have not succeeded in producing human bispecific antibodies redirected human CTL to destroy human target cells. Less
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Report
(4results)
Research Products
(25results)
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[Publications] Mora, T.M., Usuba, O., Kuzu, H., Kuzu, Y., Schulman, J., and Bona, C.A.: "Inhibition of multicycle influenza virus replication by hybrid antibody-directed cytotoxic T lymphocyte lysis." J.Immunol.146. 321-326 (1991)
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