Department of Systems Immunology and Institute of Antibody Research, College of Biomedical Science, Kangwon National University, Chuncheon 200-701, Korea.
Exp Mol Med. 2012 Apr 30;44(4):293-302. doi: 10.3858/emm.2012.44.4.027.
Intrahepatic cholangiocarcinoma (ICC), a malignant tumor derived from the intrahepatic bile duct epithelium, has a poor prognosis and is refractory to conventional chemotherapy and radiation therapy. Thus, there is an urgent need to develop new effective therapeutic strategies for this disease. We previously found that L1 cell adhesion molecule (L1CAM) plays an important role in tumor progression of ICC, and we generated a murine mAb, A10-A3 (IgG1), that binds to the Ig1 domain of L1CAM. In the present study, we further characterized A10-A3, constructed a chimeric A10-A3 antibody (cA10-A3) containing the constant regions of human IgG1, and evaluated the therapeutic potential in a human ICC xenograft nude mice model. The affinities (KD) of A10-A3 and cA10-A3 for soluble L1CAM were 1.8 nM and 1.9 nM, respectively, as determined by competition ELISA. A10-A3 inhibited L1CAM homophilic binding and was slowly internalized into the tumor cells, but it did not significantly inhibit proliferation of ICC cells in vitro. cA10-A3 mediated antibody- dependent cell-mediated cytotoxicity in vitro and displayed anti-tumor activity in the ICC animal model. These results suggest that the humanized A10-A3 antibody may have potential as an anticancer agent for the treatment of ICC.
肝内胆管癌（ICC）是一种来源于肝内胆管上皮的恶性肿瘤，其预后较差，对常规化疗和放疗有抵抗性。因此，迫切需要为这种疾病开发新的有效治疗策略。我们之前发现 L1 细胞黏附分子（L1CAM）在 ICC 的肿瘤进展中起重要作用，我们生成了一种与 L1CAM 的 Ig1 结构域结合的鼠源性单克隆抗体 A10-A3（IgG1）。在本研究中，我们进一步对 A10-A3 进行了表征，构建了包含人 IgG1 恒定区的嵌合 A10-A3 抗体（cA10-A3），并在人 ICC 异种移植裸鼠模型中评估了其治疗潜力。竞争 ELISA 测定 A10-A3 和 cA10-A3 对可溶性 L1CAM 的亲和力（KD）分别为 1.8 nM 和 1.9 nM。A10-A3 抑制了 L1CAM 同种型结合，并缓慢内化到肿瘤细胞中，但它并没有显著抑制 ICC 细胞在体外的增殖。cA10-A3 在体外介导抗体依赖的细胞介导的细胞毒性，并在 ICC 动物模型中显示出抗肿瘤活性。这些结果表明，人源化的 A10-A3 抗体可能具有作为治疗 ICC 的抗癌剂的潜力。
