Exp Mol Med.  2012 Apr;44(4):293-302. 10.3858/emm.2012.44.4.027.

A chimeric antibody to L1 cell adhesion molecule shows therapeutic effect in an intrahepatic cholangiocarcinoma model

• Lee ES
• Jeong MS
• Singh R
• Jung J
• Yoon H
• Min JK
• Kim KH
• Hong HJ

• KMID: 1365906
• DOI: http://doi.org/10.3858/emm.2012.44.4.027

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 (K D) 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.

Keyword

immunization, passive; intrahepatic cholangiocarcinoma; neural cell adhesion molecule L1

MeSH Terms

Animals
Antibodies, Monoclonal/genetics/*immunology
Antibody-Dependent Cell Cytotoxicity
Bile Ducts, Intrahepatic/drug effects/immunology/pathology
CHO Cells
Cell Adhesion/drug effects
Cell Proliferation/drug effects
Cholangiocarcinoma/*drug therapy/immunology/pathology
Cricetinae
Disease Models, Animal
Endocytosis/drug effects
Humans
Immunoglobulin G/genetics/*immunology
Liver Neoplasms/*drug therapy/immunology/pathology
Mice
Mice, Nude
Neoplasm Transplantation
Neural Cell Adhesion Molecule L1/genetics/*immunology/metabolism
Protein Binding
Protein Structure, Tertiary
Recombinant Fusion Proteins/immunology/metabolism/*therapeutic use