title: A chimeric antibody to L1 cell adhesion molecule shows therapeutic effect in an intrahepatic cholangiocarcinoma model.
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.
authors.affiliation: Department of Systems Immunology and Institute of Antibody Research, College of Biomedical Science, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Eung Suk
authors.initials: ES
authors.lastname: Lee
authors.forename: Mun Sik
authors.initials: MS
authors.lastname: Jeong
authors.forename: Rohit
authors.initials: R
authors.lastname: Singh
authors.forename: Juyeon
authors.initials: J
authors.lastname: Jung
authors.forename: Hyunho
authors.initials: H
authors.lastname: Yoon
authors.forename: Jeong Ki
authors.initials: JK
authors.lastname: Min
authors.forename: Kyung Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Hong
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016466:CHO Cells; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006224:Cricetinae; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D039842:Neural Cell Adhesion Molecule L1; D011993:Recombinant Fusion Proteins