权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Establishment of a new human monoclonal antibody using mice that produce complete human antibodies and applications to cancer treatment

利用产生完整人源抗体的小鼠建立新型人源单克隆抗体及其在癌症治疗中的应用

基本信息

批准号：
14207065
负责人：
NOZAWA Shiro
金额：
$ 18.89万
依托单位：
KEIO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

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 cancerKM 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 … More 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 cancerKM 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

我们的研究小组通过将完整的人类抗体基因引入小鼠体内，建立了能够产生完整的人类抗体并保留抗体多样性的KM小鼠。这些小鼠能够通过抗原免疫产生人类抗体。目前的研究旨在利用这些小鼠建立高特异性靶向癌细胞的人单克隆抗体（hMab），并将这些hMab用于癌症的诊断和治疗。1）子宫内膜癌hMab的建立用子宫内膜癌细胞系SNG-S免疫KM小鼠，并通过常规筛选选择与子宫内膜癌细胞反应的克隆（克隆10-9D）方法并命名为HMMC-1。免疫组织化学染色显示，HMMC-1在子宫内膜腺癌标本、宫颈腺癌标本、上皮性卵巢癌标本、腹膜癌标本中的阳性率分别为54.6%、76.9%、75%和87.5%。此外，这种单克隆抗体不会与增殖期或分泌期的正常子宫内膜或正常宫颈样本发生反应。因此，发现该抗体能够特异性识别苗勒管癌和苗勒管相关癌症，具有高特异性。碳水化合物分析确定该抗体的表位结构是具有扩展核心1结构的O-连接碳水化合物结构，是在人类中表达有限的碳水化合物结构。2)卵巢癌hMab的建立用卵巢透明细胞免疫KM小鼠腺癌细胞系RMG-1，并通过与1)相同的方法，选择与卵巢透明细胞腺癌细胞反应的克隆（克隆2-10A）并命名为HMOCC-1。该抗体在 83.2% (84/101) 的上皮性卵巢癌标本中呈免疫组织化学阳性；根据组织病理学亚型，浆液性腺癌、子宫内膜样腺癌、透明细胞腺癌和粘液性腺癌的阳性率分别为 72.2%、73.9%、90% 和 90%。在体外，发现该抗体可抑制腹膜间皮细胞和 RMG-1 细胞的附着。该抗体的表位结构被确定为具有不包含唾液酸的碳水化合物结构的糖蛋白。较少的