Development of complete human monoclonal antibodies and immune complexes for use in the treatment of cancers

开发用于治疗癌症的完整人单克隆抗体和免疫复合物

• 批准号: 16390478
• 负责人: AOKI Daisuke
• 金额: $ 9.15万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390478/
• 关键词: human monoclonal antibody; endometrial cancer; lymph node metastasis; ovarian cancer; complement-dependent cytotoxicity; carbohydrate antigen; hCG; 標的治療; ヒト型モノクローナル抗体; hCG; extended core-1

Antibody-based therapy has recently gathered attention as a new targeted therapy for cancer and the field of antibody engineering has shown remarkable progress. Human monoclonal antibodies (Mab) developed in our laboratory, using mice that produce complete human antibodies (KM mouse), demonstrate almost no immunogenicity towards humans and do not develop antibodies towards foreign proteins even with repeated administration. The following antibodies were developed during this study period and investigations into their possible clinical applications were performed.1. The HMMC-1 (human monoclonal antibody against mullerian cancer) was established using an endometrial cancer cell line as immunogen. The antibody demonstrates high specificity towards endometrial and ovarian cancer, while it shows complement-dependent cytotoxicity in vitro. The HMMC-1 epitope was shown to be a novel carbohydrate structure unique to gynecologic cancers. Using surgical specimens from endometrial cancer, the ant … More ibody demonstrated stronger immunohistochemical staining in metastatic tumors compared to primary tumors in the same patient. In addition, using an in vivo lymph node metastasis mouse model developed in our laboratory, the antibody showed an anti-tumor effect towards retroperitoneal lymph node metastasis formed from orthotopically-implanted primary uterine tumors in nude mice. Thus, this antibody demonstrates anti-tumor effects towards lymph node metastasis.2. The HMOCC-1 (human monoclonal antibody against ovarian clear cell adenocarcinoma) and HMOCC-2 Mabs were developed using the ovarian clear cell adenocarcinoma cell line RMG-1 as immunogen. Both Mabs demonstrate high positive rates towards gynecologic cancers, especially ovarian cancer. The HMOCC-1 Mab demonstrates an inhibitory effect towards cell adhesion, more specifically between tumor cells and peritoneal mesothelial cells, as shown by in vitro assays. Furthermore, the HMOCC-2 Mab was shown to possess an epitope on the CAl25 molecule, often used as a marker for ovarian cancer and also demonstrates anti-tumor effects towards subcutaneous tumors implanted in nude mice.3. A Mab was developed using human hCG (human chorionic gonadotropin) as immunogen and was named 8-1A. The Mab recognizes intact hCG and did not cross-react with LH. Future studies are planned to address the possible inhibitory effects of this Mab towards the biological function of hCG. In the future, we plan to investigate the characteristics and anti-tumor effects of these antibodies and possibly test the anti-tumor effects of the various Mabs towards gynecologic cancers in the perspective of future clinical applications. Less

抗体疗法作为一种新的癌症靶向疗法最近受到关注，抗体工程领域也取得了显着的进展。我们实验室使用产生完全人抗体的小鼠（KM小鼠）开发的人单克隆抗体（Mab），对人类几乎没有免疫原性，即使重复给药也不会产生针对外源蛋白的抗体。本研究期间开发了以下抗体，并对其可能的临床应用进行了调查。 1． HMMC-1（抗缪勒管癌的人单克隆抗体）是使用子宫内膜癌细胞系作为免疫原建立的。该抗体对子宫内膜癌和卵巢癌表现出高度特异性，同时在体外表现出补体依赖性细胞毒性。 HMMC-1表位被证明是妇科癌症特有的一种新型碳水化合物结构。使用子宫内膜癌的手术标本，与同一患者的原发性肿瘤相比，蚂蚁抗体在转移性肿瘤中表现出更强的免疫组织化学染色。此外，使用我们实验室开发的体内淋巴结转移小鼠模型，该抗体对裸鼠原发性子宫肿瘤原位种植形成的腹膜后淋巴结转移显示出抗肿瘤作用。因此，该抗体表现出针对淋巴结转移的抗肿瘤作用。2． HMOCC-1（抗卵巢透明细胞腺癌的人单克隆抗体）和 HMOCC-2 Mab 是使用卵巢透明细胞腺癌细胞系 RMG-1 作为免疫原开发的。两种 Mab 对妇科癌症（尤其是卵巢癌）均表现出较高的阳性率。如体外测定所示，HMOCC-1 Mab 对细胞粘附（更具体地说是肿瘤细胞和腹膜间皮细胞之间）具有抑制作用。此外，HMOCC-2 Mab在CAl25分子上具有表位，常被用作卵巢癌的标志物，并且对裸鼠皮下移植肿瘤也具有抗肿瘤作用。 3．使用人hCG（人绒毛膜促性腺激素）作为免疫原开发了单克隆抗体，并命名为8-1A。 Mab 可识别完整的 hCG 并且不与 LH 发生交叉反应。未来的研究计划解决该 Mab 对 hCG 生物学功能可能的抑制作用。未来，我们计划研究这些抗体的特性和抗肿瘤作用，并从未来临床应用的角度可能测试各种Mab对妇科癌症的抗肿瘤作用。较少的

项目成果

Clinicopathologic manifestations of early-onset endometrial cancer in Japanese women with a familial predisposition to cancer.

有癌症家族倾向的日本女性早发子宫内膜癌的临床病理学表现。

• 发表时间: 2005
• 期刊: J Obstet Gynaecol Res 31(5)
• 作者: Yanokura M;Banno K et al.;Yamagami W et al.
• 通讯作者: Yamagami W et al.

Analysis of clinicopathologic factors predicting para-aortic lymph node metastasis in endometrial cancer

• DOI: 10.1136/ijgc-00009577-200603000-00053
• 发表时间: 2005-06
• 期刊: International Journal of Gynecologic Cancer
• 作者: H. Nomura;D. Aoki;N. Suzuki;N. Susumu;A. Suzuki;Y. Tamada;F. Kataoka;Atsushi Higashiguchi;S. Ezawa;S. Nozawa

Identification of tissue-specific vasculogenic cells originating from murine uterus

鉴定源自小鼠子宫的组织特异性血管生成细胞

• 发表时间: 2006
• 期刊: Histochem. Cell Biol. 125(6)
• 作者: Toda J;Kato S;Oshika T;Sugita G;Narumi Onodera
• 通讯作者: Narumi Onodera

HMMC-1: a humanized monoclonal antibody with therapeutic potential against Mullerian duct-related carcinomas.

HMMC-1：一种人源化单克隆抗体，具有治疗苗勒氏管相关癌的潜力。

• DOI: 10.1158/1078-0432.ccr-04-0802
• 发表时间: 2004
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Nozawa,Shiro;Aoki,Daisuke;Tsukazaki,Katsumi;Susumu,Nobuyuki;Sakayori,Motoko;Suzuki,Nao;Suzuki,Atsushi;Wakita,Rie;Mukai,Makio;Egami,Yuko;Kojima-Aikawa,Kyoko;Ishida,Isao;Belot,Frederic;Hindsgaul,Ole;Fukuda,Minoru;Fukuda,Michik
• 通讯作者: Fukuda,Michik

ヒトモノクローナル抗体HMMC-1の子宮体癌リンパ節転移に対する効果についての検討

人源化单克隆抗体HMMC-1对子宫内膜癌淋巴结转移的影响研究

• 发表时间: 2006
• 期刊: 日本分子腫瘍マーカー研究会誌 21
• 作者: 古田 康;他;鈴木 淳
• 通讯作者: 鈴木 淳