Synergistic anti-tumor activity of paclitaxel with CNTO 95, a fully human monoclonal antibody that targets αv integrins

Abstract

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CNTO 95 is a fully human monoclonal antibody which binds and neutralizes αv integrins. We recently demonstrated that CNTO 95 possesses both anti-angiogenic and direct anti-tumor activity against human melanoma xenografts in vivo. In the present study CNTO 95 was combined with the chemotherapeutic compound paclitaxel, which itself exhibits both anti-angiogenic and anti-tumor effects. Treatment of human endothelial cells in culture with paclitaxel and CNTO 95 resulted in a dose-dependent decrease in cell proliferation and an increase in apoptosis. These effects were more pronounced with the combination than with either agent alone. Similarly, the combination of paclitaxel with CNTO 95 was more effective than either agent alone in reducing proliferation and inducing apoptosis of human melanoma cells. For in vivo analysis, nude rats were inoculated subcutaneously with human melanoma cells, and experimental therapy was initiated when tumors reached 150-200 mm³. In this model, CNTO 95 inhibits tumor cell and host angiogenic integrins. Intensive dosing with paclitaxel for one week (escalating to 15 mg/kg) caused a 52% reduction in tumor growth by day 16, and provided a tumor growth delay of 12 days. While CNTO 95 by itself had little effect in this model, the combination of paclitaxel and CNTO 95 (10 mg/kg weekly) showed greatly enhanced activity, causing a 71% reduction in tumor size by day 16 and a growth delay of 24 days. Fractional tumor volume analysis revealed synergy between the two agents. Together, these data support the hypothesis that combining biologic agents with chemotherapeutics will enhance anti-tumor efficacy.