2003 Fiscal Year Annual Research Report

完全ヒト型抗体産生マウスを用いたヒト型モノクローナル抗体の作製と癌治療への応用

Research Project

Project/Area Number	14207065
Research Institution	KEIO UNIVERSITY
Principal Investigator	野澤志朗慶應義塾大学, 医学部, 教授 (90051557)
Co-Investigator(Kenkyū-buntansha)	鈴木直慶應義塾大学, 医学部, 助手 (90246356) 進伸幸慶應義塾大学, 医学部, 助手 (90206459) 塚崎克己慶應義塾大学, 医学部, 助教授 (40118972) 石田功キリンビール(株), 医薬カンパニー企画部, 部長代理(研究職) 福地剛慶應義塾大学, 医学部, 助手 (70245554)
Keywords	ヒトモノクローナル抗体 / KM mouse / ミサイル療法 / 子宮体癌 / 卵巣癌 / 糖鎖抗原
Research Abstract	我々の研究グループはヒト抗体遺伝子全長をマウスへ導入して、抗体多様性を維持したまま完全ヒト抗体を産生するKM mouseを作製し、抗原刺激によってヒト抗体を獲得できる新しい技術を世界に先駆けて確立した。本研究ではこのマウスを用いたヒトモノクローナル抗体(hMab)の作製を試み、癌細胞のみを高い確率で認識するhMabを選別することによって、癌の診断および治療に応用することを目的とした。本年度は、昨年度に得られた成果をもとにさらに研究を進め、以下のような結果を得た。 1.昨年度の本研究により、KM mouseを子宮体癌培養細胞SNG-Sで免疫することによって、HMMC-1 (hMab against Murellian related cancer)の作製に成功した。本年度は生化学的手法による抗原決定基の構造解析を行った結果、ヒトでの体内分布が極めて限られるextended core 1構造を有するo-glycanであることが判明した。本抗体の反応性としては、子宮体癌(54.6%)、子宮頸部腺癌(76,9%)、卵巣癌(75%)、腹膜癌(87,5%)で陽性反応が認められたが、正常子宮内膜や他の正常組織あるいは癌との反応性はほとんど認められなかったことから、本抗体はいわゆるMurellian cancerをはじめとする胎児体腔上皮由来の癌に高い特異性を示すものと考えられた。 2.さらに、卵巣明細胞腺癌培養細胞RMG-1を免疫し、HMOCC-1 (hMab against ovarian clear cell carcinoma)を作製した。卵巣明細胞腺癌あるいは粘液性腺癌組織に高い陽性率(70〜80%)を示すだけでなく、腹膜中皮細胞とRMG-1との接着を阻害することがin vitroで確認された。目下のところ、その抗原分子はシアル酸を含まない糖鎖を有する糖蛋白質であることが示唆されている。

Research Products

(15 results)

All Other

All Publications (15 results)

[Publications] Yutaka Tamada, et al.3: "Model for paraaortic lymph node metastasis produced by orthotopic implantation of ovarian carcinoma cells in athymic nude mice."Eur.J.Cancer. 40・1. 158-163 (2003)
[Publications] Jun Nakayama, et al.11: "Implantation-dependent expression of trophinin by maternal fallopian tube epithelia during tubal pregnancies : possible role of human chorionic gonadotrophin on ectopic pregnancy."Am.J.Pathol.. 163・6. 2211-2219 (2003)
[Publications] Akita Hirasawa, et al.7: "Unfavorable prognostic factors associated with high frequency of micorosatellite instability and comparative genomic hybridization analysis in endometrial cancer."Clin.Cancer Res.. 9・15. 5675-5682 (2003)
[Publications] Takuma Fujii, et al.9: "Peptides inhibitory for the transcriptional regulatory function of human papillomavirus E2."Clin.Cancer Res.. 9・14. 5423-5428 (2003)
[Publications] Kyoko Takehara, et al.8: "Estrogen sulfotransferase and sulfatase : roles in the regulation of estrogen activity in human uterine endometrial carcinomas."Cancer Science. 94・10. 871-875 (2003)
[Publications] Eiko Saitoh, et al.4: "Galactosyltransferase associated with tumor in patients with ovarian cancer : factors involved in elevation of serum galactosyltransferase."Int.J.Oncol.. 23・2. 303-310 (2003)
[Publications] Kouji Banno, et al.8: "Identification of germline MSH2 gene mutations in endometrial cancer not fulfilling the new clinical criteria for hereditary nonpolyposis colorectal cancer."Cancer Genet.Cytogenet.. 146・1. 58-65 (2003)
[Publications] Nobuo Masumoto, et al.10: "p16^<INK4a> overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix."Pathology. 34・8. 778-783 (2003)
[Publications] Mitsuya Ishikawa, et al.10: "Correlation of p16^<INK4A> overexpression with human papillomavirus infection in cervical adenocarcinomas."Int.J.Gynecol.Pathol.. 22・4. 378-385 (2003)
[Publications] Ken Ishitani, et al.5: "p54^<nrb> acts as a transcriptional coactivator for activation function 1 of the human androgen receptor."Biochem.Biophys.Res.Commun.. 306. 660-665 (2003)
[Publications] Akira Hirasawa, et al.8: "Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPMID and APPBP2 as likely amplification targets."Clin.Cancer Res.. 9. 1995-2004 (2003)
[Publications] Nobuyuki Susumu, et al.7: "Subcellular lacalization of galactosyltransferase associated with tumors in endometrial and ovarian cancer cells."Acta Histchem.Cytochem.. 36・3. 205-214 (2003)
[Publications] Nobuo Masumoto, et al.8: "Papanicolaou tests and molecular analyses using new fluid-based specimen collection technology in 3000 Japanese women."Br.J.Cancer. 88・12. 1883-1888 (2003)
[Publications] Masatoshi Yokoyama, et al.11: "Prognostic factors associated with the clinical outcome of cervical intraepithelial neoplasia : a cohort study in Japan."Cancer Letters. 192・2. 171-179 (2003)
[Publications] 野澤志朗, 他1名: "「1億人の家庭の医学」子宮がん,卵巣がん,絨毛がん,外陰がん"主婦の友社. 392(52-61) (2003)

2003 Fiscal Year Annual Research Report

完全ヒト型抗体産生マウスを用いたヒト型モノクローナル抗体の作製と癌治療への応用

Principal Investigator

野澤 志朗 慶應義塾大学, 医学部, 教授 (90051557)

Research Products

[Publications] Yutaka Tamada, et al.3: "Model for paraaortic lymph node metastasis produced by orthotopic implantation of ovarian carcinoma cells in athymic nude mice."Eur.J.Cancer. 40・1. 158-163 (2003)

[Publications] Jun Nakayama, et al.11: "Implantation-dependent expression of trophinin by maternal fallopian tube epithelia during tubal pregnancies : possible role of human chorionic gonadotrophin on ectopic pregnancy."Am.J.Pathol.. 163・6. 2211-2219 (2003)

[Publications] Akita Hirasawa, et al.7: "Unfavorable prognostic factors associated with high frequency of micorosatellite instability and comparative genomic hybridization analysis in endometrial cancer."Clin.Cancer Res.. 9・15. 5675-5682 (2003)

[Publications] Takuma Fujii, et al.9: "Peptides inhibitory for the transcriptional regulatory function of human papillomavirus E2."Clin.Cancer Res.. 9・14. 5423-5428 (2003)

[Publications] Kyoko Takehara, et al.8: "Estrogen sulfotransferase and sulfatase : roles in the regulation of estrogen activity in human uterine endometrial carcinomas."Cancer Science. 94・10. 871-875 (2003)

[Publications] Eiko Saitoh, et al.4: "Galactosyltransferase associated with tumor in patients with ovarian cancer : factors involved in elevation of serum galactosyltransferase."Int.J.Oncol.. 23・2. 303-310 (2003)

[Publications] Kouji Banno, et al.8: "Identification of germline MSH2 gene mutations in endometrial cancer not fulfilling the new clinical criteria for hereditary nonpolyposis colorectal cancer."Cancer Genet.Cytogenet.. 146・1. 58-65 (2003)

[Publications] Nobuo Masumoto, et al.10: "p16^<INK4a> overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix."Pathology. 34・8. 778-783 (2003)

[Publications] Mitsuya Ishikawa, et al.10: "Correlation of p16^<INK4A> overexpression with human papillomavirus infection in cervical adenocarcinomas."Int.J.Gynecol.Pathol.. 22・4. 378-385 (2003)

[Publications] Ken Ishitani, et al.5: "p54^<nrb> acts as a transcriptional coactivator for activation function 1 of the human androgen receptor."Biochem.Biophys.Res.Commun.. 306. 660-665 (2003)

[Publications] Akira Hirasawa, et al.8: "Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPMID and APPBP2 as likely amplification targets."Clin.Cancer Res.. 9. 1995-2004 (2003)

[Publications] Nobuyuki Susumu, et al.7: "Subcellular lacalization of galactosyltransferase associated with tumors in endometrial and ovarian cancer cells."Acta Histchem.Cytochem.. 36・3. 205-214 (2003)

[Publications] Nobuo Masumoto, et al.8: "Papanicolaou tests and molecular analyses using new fluid-based specimen collection technology in 3000 Japanese women."Br.J.Cancer. 88・12. 1883-1888 (2003)

[Publications] Masatoshi Yokoyama, et al.11: "Prognostic factors associated with the clinical outcome of cervical intraepithelial neoplasia : a cohort study in Japan."Cancer Letters. 192・2. 171-179 (2003)

[Publications] 野澤 志朗, 他1名: "「1億人の家庭の医学」子宮がん,卵巣がん,絨毛がん,外陰がん"主婦の友社. 392(52-61) (2003)

野澤志朗慶應義塾大学, 医学部, 教授 (90051557)

[Publications] 野澤志朗, 他1名: "「1億人の家庭の医学」子宮がん,卵巣がん,絨毛がん,外陰がん"主婦の友社. 392(52-61) (2003)