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

我们的研究小组通过将完整的人抗体基因导入小鼠，建立了产生完整的人抗体同时保留抗体多样性的KM小鼠。这些小鼠能够通过抗原免疫产生人抗体。本研究的目的是利用这些小鼠建立特异性靶向癌细胞的人源性单克隆抗体（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，选择与子宫内膜癌细胞反应的克隆（克隆10-9D），命名为HMMC-1。HMMC-1在子宫内膜腺癌、宫颈腺癌、卵巢上皮癌和腹膜癌中的阳性率分别为54.6%、76.9%、75%和87.5%。富尔泰姆 关于我们 因此，该单克隆抗体不与增殖期或分泌期正常子宫内膜或正常宫颈样品反应。碳水化合物分析确定该抗体的表位结构是具有延伸的核心1结构的O-连接的碳水化合物结构，2）抗卵巢癌hMab的建立用卵巢透明细胞腺癌细胞系RMG-1免疫KM小鼠，1的方法，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）的上皮性卵巢癌组织中呈化学阳性，在浆液性、类浆液性、透明细胞和粘液腺癌组织中的阳性率分别为72.2%、73.9%、90%和90%。该抗体的表位结构被确定为具有不包括唾液酸的碳水化合物结构的糖蛋白。少

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