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

抗体治疗作为一种新的肿瘤靶向治疗方法，近年来引起了人们的广泛关注，抗体工程领域也取得了显著的进展。我们实验室开发的人类单抗(Mab)，使用能产生完全人类抗体的小鼠(KM小鼠)，对人类几乎没有免疫原性，即使重复给药也不会产生对外源蛋白的抗体。在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。以子宫内膜癌细胞株为免疫原，建立了人抗苗勒癌单抗HMMC-1。该抗体对子宫内膜癌和卵巢癌表现出高度的特异性，在体外表现出补体依赖性的细胞毒作用。HMMC-1表位是妇科肿瘤特有的一种新型碳水化合物结构。使用来自子宫内膜癌的手术标本，蚂蚁…在同一患者中，更多的人在转移性肿瘤中表现出比原发肿瘤更强的免疫组织化学染色。此外，利用本实验室建立的小鼠体内淋巴结转移模型，该抗体对裸鼠原发子宫肿瘤原位移植所形成的腹膜后淋巴结转移具有一定的抗肿瘤作用。因此，该抗体具有抗肿瘤淋巴转移的作用。以人卵巢透明细胞腺癌细胞株RMG-1为免疫原，制备了人抗卵巢透明细胞腺癌单抗HMOCC-1和HMOCC-2单抗。这两种单抗对妇科癌症，特别是卵巢癌的阳性率都很高。体外实验表明，HMOCC-1单抗对细胞黏附有抑制作用，尤其是肿瘤细胞与腹膜间皮细胞之间的黏附。此外，HMOCC-2单抗在CAl25分子上具有表位，CAl25分子通常被用作卵巢癌的标志，并且对裸鼠皮下移植瘤也具有抗肿瘤作用。以人绒毛膜促性腺激素(HCG)为免疫原，制备了一株单抗，命名为8-1A。该单抗可识别完整的hCG，且不与黄体生成素发生交叉反应。未来的研究计划解决该单抗对hCG生物学功能可能的抑制作用。在未来，我们计划研究这些抗体的特性和抗肿瘤作用，并可能从未来临床应用的角度测试各种单抗对妇科肿瘤的抗肿瘤作用。较少

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