Tissue factor (TF) is a cell surface receptor that plays a critical role in hemostasis by acting as the primary initiator of the extrinsic clotting cascade. TF has been shown to be overexpressed on tumor cells and intra-tumoral endothelial cells in most major tumor types. TF activity is thought to be a major contributor to the thrombotic complications of cancer and plays an important role in tumor growth, metastasis, and angiogenesis. In these studies we sought to determine the anti-tumor and anti-metastatic activities of the anti-TF antibody CNTO 859. CNTO 859 is a humanized monoclonal antibody that binds to TF on cells with high affinity and inhibits TF activity by preventing Factor X from binding to the TF-Factor VIIa complex. CNTO 859 inhibits TF initiated coagulation of human plasma in vitro with an EC50 of 10 μg/mL. In the studies presented here we demonstrate that anti-TF therapy with CNTO 859 significantly inhibits the metastasis and growth of MDA-MB-231 human breast carcinoma xenografts in SCID/Beige mice. Pre-treatment of SCID/Beige mice with CNTO 859 (20 mg/kg, i.v.) two hours prior to tumor cell challenge prevented lung surface colonization by human MDA-MB-231 breast carcinoma cells introduced via the lateral tail vein. Inhibition of metastasis formation was virtually complete with approximately 1000-fold fewer observable lesions in the CNTO 859 treated groups (either single bolus or q7d x 8) relative to saline (p=0.006) or control antibody (p=0.004) treated cohorts (Wilcoxon rank sum test, n=8). In a second model, MDA-MB-231 human breast carcinoma cells were orthotopically implanted into the mammary fat pad of SCID/Beige mice. Intravenous treatment with CNTO 859 was initiated 3 days after tumor cell implantation. Animals were dosed at 20, 10, 5, 1, and 0.1 mg/kg (q7d x 8). Tumor growth was potently inhibited by greater than 90% at all dose levels relative to control antibody treated animals (0.0031<p< 0.0106, Wilcoxon two-sample test using t-distribution). These results suggest an important role for TF in tumor metastasis and growth in these models and that CNTO 859 may have utility in treating human cancers in the clinical setting.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]