Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 19; pp. 8809 - 8817
• Main Authors: BLUMENTHAL, Rosalyn D, HANSEN, Hans J, GOLDENBERG, David M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2005
• Subjects: Animals; Antibodies - immunology; Antibodies - pharmacology; Antigens, CD - immunology; Biological and medical sciences; Carcinoembryonic Antigen - immunology; Cell Adhesion - drug effects; Cell Adhesion - immunology; Cell Adhesion Molecules - antagonists & inhibitors; Cell Adhesion Molecules - immunology; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - immunology; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Dissemination; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - immunology; Female; GPI-Linked Proteins; Humans; Lung Neoplasms - immunology; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Medical sciences; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Tumor cell; Tumors; Xenograft Model Antitumor Assays; Carcinoembryonic antigen; Target; Tumor associated antigen; Targeting; Oncofetal antigen; Antimetastatic agent; Malignant tumor; Monoclonal antibody; Inhibition; Metastasis; Adhesion; Invasion
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-0420

CEACAM5 and CEACAM6 are overexpressed in many cancers and are associated with adhesion and invasion. The effects of three monoclonal antibodies targeting different epitopes on these antigens (NH2-terminal [MN-3] and A1B1 domains [MN-15] shared by CEACAM5 and CEACAM6 and the A3B3 domain [MN-14] restricted to CEACAM5) were evaluated in migration, invasion, and adhesion assays in vitro using a panel of human pancreatic, breast, and colonic cancer cell lines, and in the GW-39 human colonic micrometastasis model in vivo. MN-3 Fab' and MN-15 Fab' were both effective at inhibiting cell migration. MN-15 Fab' treatment inhibited invasion, reducing cell penetration through an extracellular matrix (ECM). MN-3 Fab' also decreased invasion but was less effective than MN-15 Fab' in four of five cell lines. All three monoclonal antibody (mAb) Fabs decreased adhesion of tumor cells to endothelial cells by 49% to 58%. MN-15 Fab' but not MN-3 or MN-14 Fabs induced a decrease in adhesion of three of six cell lines to the ECM protein, fibronectin, but adhesion to vitronectin, laminin, collagen-I, and collagen-IV was not affected. In vivo studies showed that treatment with MN-3 Fab' or MN-15 Fab' of mice implanted with GW-39 human colonic cancer cells increased their survival (P < 0.025 and P < 0.01, respectively). These studies show that antibody Fabs that target either CEACAM5 or CEACAM6 affect cell migration, cell invasion, and cell adhesion in vitro, and that MN-15 and MN-3 Fabs have antimetastatic effects in vivo, resulting in improved survival of mice with metastases. Thus, blocking the N and A1B1 domains of CEACAM5/CEACAM6 can impede the metastatic process.