Abstract
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.
Highlights
Cholangiocarcinoma is a malignant tumor that arises from the bile duct epithelium
Internalization of A10-A3 was not detected in Choi-CK and SCK cells, probably because these cells express lower levels of L1 cell adhesion molecule (L1CAM) compared to SCK-L1 cells (Figure 2A)
Since we observed that chimeric A10-A3 antibody (cA10-A3) did not induce antibodydependent cell-mediated cytotoxicity (ADCC) against the Choi-CK cells in vitro, we examined whether the Choi-CK cells in the xenograft expressed a higher level of L1CAM compared to that of the cells cultured in vitro
Summary
Cholangiocarcinoma is a malignant tumor that arises from the bile duct epithelium. Cholangiocarcinoma is classified anatomically into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) that have different risk factors, pathogeneses, and clinical features due to the distinct development and differentiation of intrahepatic and extrahepatic bile duct epithelium (Nakeeb et al, 1966; Shiojiri, 1997; Shaib et al, 2007). ICC occurs at a higher incidence in Southeast Asia than in Europe and North America, but the incidence and mortality rates are increasing worldwide (Nakeeb et al, 1966; Patel, 2001; Taylor-Robinson et al, 2001). Because of a lack of early diagnosis, most patients have occult metastasis or advanced local disease on clinical presentation (Lazaridis and Gores, 2005).
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