| Project/Area Number |
14207065
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | KEIO UNIVERSITY |
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Principal Investigator |
NOZAWA Shiro Keio University, School of Medicine, Professor, 医学部, 教授 (90051557)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Nao Keio University, School of Medicine, Assistant, 医学部, 助手 (90246356)
SUSUMU Nobuyuki Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (90206459)
TSUKAZAKI Katsumi Keio University, School of Medicine, Associated Professor, 医学部, 助教授 (40118972)
ISHIDA Isao Kirin Brewery Co. Ltd., Planning Dept. Pharmaceutical Division, Research Planning Section, Senior Manager, 医薬カンパニー企画部, 部長代理
FUKUCHI Takeshi Keio University, School of Medicine, Assistant, 医学部, 助手 (70245554)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥29,510,000 (Direct Cost: ¥22,700,000、Indirect Cost: ¥6,810,000)
Fiscal Year 2003: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
Fiscal Year 2002: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
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| Keywords | KM mouse / human monoclonal antibody / endometrial cancer / O-glycan / ovarian cancer / ミサイル療法 / 糖鎖抗原 / ヒト型モノクローナル抗体 / Cross-bred TC mouse |
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| Research Abstract |
Our research group established KM mice that produce complete human antibodies while retaining antibody diversity by introduction of the complete human antibody gene to mice. These mice are able to produce human antibodies with immunization by antigen. The current investigation aimed to establish human monoclonal antibodies (hMab) that would target cancer cells with high specificity using these mice and to use these hMabs in the diagnosis and treatment of cancer.
1) Establishment of a hMab to endometrial cancer
KM mice were immunized with the endometrial cancer cell line SNG-S and a clone was selected that reacts with endometrial cancer cells (clone 10-9D) by conventional screening methods and named HMMC-1. Immunohistochemical staining revealed that the reactivity of HMMC-1 was positive in 54.6% of uterine endometrial adenocarcinoma specimens, 76.9% of uterine cervical adenocarcinoma specimens, 75% of epithelial ovarian cancer specimens, and 87.5% of peritoneal cancer specimens. Furthermo
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re, this monoclonal antibody does not react with either proliferative or secretory phase normal endometrium or normal uterine cervical samples. Thus this antibody was found to specifically recognize mullerian cancers and mullerian duct related cancers with high specificity.
Carbohydrate analysis determined that the epitope structure for this antibody is a O-linked carbohydrate structure with an extended core 1 structure, a carbohydrate structure with limited expression in humans.
2) Establishment of a hMab to ovarian cancer
KM mice were immunized with the ovarian clear cell adenocarcinoma cell line RMG-1 and by the same methodology of 1), a clone was selected that reacts with ovarian clear cell adenocarcinoma cells (clone 2-10A) and named HMOCC-1. This antibody is immunohistochemically positive with 83.2% (84/101) of epithelial ovarian cancer specimens ; by histopathological subtype, it is positive with 72.2%, 73.9%, 90% and 90% of serous, endometrioid, clear cell, and mucinous adenocarcinoma respectively.
In vitro, this, antibody was found to inhibit the attachment of peritoneal mesothelial cells and RMG-1 cells. The epitope structure of this antibody was determined to be a glycoprotein with a carbohydrate structure that does not include sialic acid. Less
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