Tissue factor as an anti-cancer target: inhibition of tumor growth and metastasis by anti-tissue factor monoclonal antibodies blocking factor X activation

699 We report the inhibitory effects of an anti-human tissue factor (TF) monoclonal antibody (mAb, H36, a murine mAb, and hOAT, the humanized form of H36) on primary tumor growth and metastasis in animal models of human cancer. H36/hOAT inhibit TF/FVIIa-dependent activation of Factor X (FX) or FIX by blocking the binding of FX (or IX) to TF or TF/FVIIa complex. The cell lines used in the studies (MDA-MB-435/TF, MCF-7/TF, DU145L1, HT29Lu3 and A375) all express functional human TF. Subcutaneous injection of MCF-7/TF cells resulted in larger primary tumors with extensive blood vessels when compared with MCF-7 parental cells. Matrigel plug assay demonstrated that rhuTF promoted neovascularization and treatment with anti-TF mAb inhibited the process. Complete inhibition or a significant reduction ( P P P = 0.004, logrank test) in MDA-MB-435/TF model. Conclusion: Anti-human TF mAbs (H36 and hOAT) inhibited primary tumor growth and metastasis in mouse models of cancers. Since majority of cancer types overexpress TF, our studies support the use of anti-TF mAbs that inhibit TF/FVIIa-dependent activation of FX (or IX) by blocking its binding to TF or TF/FVIIa complex or blocking the formation of TF/FVIIa/FXa complex for cancer treatment and prevention in humans.