CNTO 95, a fully human anti αv integrin antibody, inhibits cell signaling, migration, invasion, and spontaneous metastasis of human breast cancer cells

Abstract

CNTO 95 is a fully human monoclonal antibody that recognizes alphav integrins. Previous studies have shown that CNTO 95 exhibits both anti-tumor and anti-angiogenic activities (Trikha M et al., Int J Cancer 110:326-335, 2004). In this study we investigated the biological activities of CNTO 95 on breast tumor cells both in vitro and in vivo. In vitro treatment with CNTO 95 decreased the viability of breast tumor cells adhering to vitronectin. CNTO 95 inhibited tumor cell adhesion, migration, and invasion in vitro. CNTO 95 treatment also induced tyrosine dephosphorylation of focal adhesion kinase (FAK), and the docking protein paxillin that recruits both structural and signaling molecules to focal adhesions (Turner CE, Int J Biochem Cell Biol 30:955-959, 1998; O'Neil GM et al., Trends Cell Biol 10:111-119, 2000). These results suggest that CNTO 95 inhibits breast tumor cell growth, migration and invasion by interruption of alphav integrin mediated focal adhesions and cell motility signals. In vivo studies of CNTO 95 were conducted in an orthotopic breast tumor xenograft model. Treatment with CNTO 95 resulted in significant inhibition of both tumor growth and spontaneous metastasis of MDA-MB-231 cells to the lungs. CNTO 95 also inhibited lung metastasis in a separate experimental (tail vein injection) model of metastasis. The results presented here demonstrate the anti-tumor and anti-metastatic activities of CNTO 95 in breast cancer models and provide insight into the cellular and molecular mechanisms mediating its inhibitory effects on metastasis.

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

“…Although the antiangiogenic and radiosensitizing effects of intetumumab are not unique, intetumumab has the added advantage over many other antiangiogenic agents in development, such as inhibiting the development of metastases by targeting the αv integrin receptors and blocking its downstream cell adhesion signaling pathway (4). Here, we further show the ability of intetumumab to inhibit the subsequent development of pulmonary metastases in the NSCLC A549 model following either i.v.…”

“…Preclinical studies have shown that intetumumab exhibits antiangiogenic and antitumor activity in human cancer xenograft models in nude mice (1)(2)(3). Intetumumab has been reported to inhibit cell adhesion, migration, invasion, and proliferation of endothelial cells and tumor cells in vitro and tumor metastasis in vivo in nude mice with human breast cancer xenografts by inactivating the focal adhesion kinase (FAK) and the docking protein paxillin (1,4). We have previously shown that intetumumab is a potential radiation sensitizer when used in combination with fractionated radiation therapy in human cancer xenograft models in nude mice (5).…”

Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

“…Among these, ␣v␤3 and ␣v␤6 could be the targets because both of them act as the important receptors for fibronectin, and both of them are deeply implicated in the promotion of the cancer cell metastasis (52)(53)(54)(55). One more important molecule that could not be ignored is E-cadherin, which plays critical roles in cell-cell adhesion.…”

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

“…Many of the antibodies in development or currently marketed recognize membraneassociated antigens (28,32,37,(71)(72)(73)(74)(75)(76)(77)(78)(79)(80). Interaction of antibodies with this class of target antigen can greatly impact their PK.…”