CNTO 859, a humanized anti‐tissue factor monoclonal antibody, is a potent inhibitor of breast cancer metastasis and tumor growth in xenograft models

Abstract

Thromboembolic complications are frequently associated with advanced cancer. Interestingly, one of the major initiators of blood coagulation, tissue factor (TF), is reported to be overexpressed in several tumor types and can be found on both tumor cells and tumor vasculature. Although the exact mechanisms have yet to be elucidated, TF expressed on tumor cells can trigger intracellular signaling events through various pathways that can lead to tumor angiogenesis, proliferation, and metastasis. There exists preclinical evidence that disruption of TF dependent signaling can effectively inhibit tumor cell migration, metastasis, and angiogenesis. Here, we report for the first time that an antibody to tissue factor can also prevent tumor growth in vivo. Prophylactic administration of CNTO 859, a humanized anti-human TF antibody, was shown to inhibit experimental lung metastasis of MDA-MB-231 human breast carcinoma cells by over 99% compared to a control antibody. Furthermore, therapeutic doses of CNTO 859 were shown to reduce tumor incidence and growth of orthotopically implanted MDA-MB-231 cells. ' 2006 Wiley-Liss, Inc.

Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease

“…The upregulation of TF in invasive breast cancers may be related to the role of TF in metastasis (Bromberg et al, 2001;Amarzguioui et al, 2006;Ngo et al, 2007). Tissue factor is highly expressed in metastatic, but not in non-metastatic breast carcinoma cells (Bluff et al, 2006), and may contribute to the metastatic process directly through the TF-FVIIa complex and/or through downstream generation of active coagulation factors (Booden et al, 2004;Palumbo et al, 2007).…”

“…Tissue factor is highly expressed in metastatic, but not in non-metastatic breast carcinoma cells (Bluff et al, 2006), and may contribute to the metastatic process directly through the TF-FVIIa complex and/or through downstream generation of active coagulation factors (Booden et al, 2004;Palumbo et al, 2007). Furthermore, TF-FVIIa signalling via PAR-2 has been shown to stimulate breast cancer cell migration (Jiang et al, 2004;Morris et al, 2006), and a humanised anti-TF monoclonal antibody (CNTO 859) inhibited experimental in vivo lung metastasis from invasive breast cancer cells by more than 99%, indicating a role for TF in breast cancer cell metastasis (Ngo et al, 2007).…”

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

“…Notably, pharmacological and genetic strategies targeting TF, FVIIa, thrombin, platelets and other coagulation mechanisms led to anti-tumor and anti-metastatic effects [61,[92][93][94][95][96], which are often comparable to other 'main stream' targeted agents [87,93].…”

Engineered Protease-resistant Antibodies with Selectable Cell-killing Functions

“…mAbs were purified using protein A columns and underwent in-house quality controls for Ͼ95% purity prior to further experimental analyses. The complementarity-determining region sequences of the humanized, complementarity-determining region-grafted anti-CD142 mAb were derived from the murine anti-human CD142 mAb TF8-5G9, which originated at the Scripps Research Institute and has been described previously (40,41).…”