Pathological expression of tissue factor confers promising antitumor response to a novel therapeutic antibody SC1 in triple negative breast cancer and pancreatic adenocarcinoma

The pathological presence of tissue factor (TF) in cancer cells promotes tumor-initiated thrombosis and cancer metastasis. We found that TF is aberrantly present in large percentage of aggressive triple negative breast cancer (TNBC) and pancreatic adenocarcinoma (PaC), two most lethal forms of malignancy that urgently need effective treatment. TF expression in TNBC clustered with higher levels of vimentin, basal-type keratins KRT5/14 and caveolin-1 but lower levels of luminal-type biomarkers. We developed a novel and specific anti-TF therapeutic antibody SC1, which displayed an exceedingly high potency against TF extracellular domain (EC : 0.019 nM), TF-positive TNBC- or PaC cells (EC : 2.5 nM), intracellular protease activated receptor 2 (PAR2) signaling (IC : 2-3 nM) and tumor-initiated coagulation (IC : 100 nM) achieving >5000 fold target selectivity. Following a weekly intravenous administration, SC1-MMAE and its humanized hSC1-MMAE inhibited TNBC- and PaC tumor growth achieving MED of 0.3-1 mg/kg and were both well tolerated. Thus, the prevalent TF expression in TNBC and PaC renders these challenging tumors highly susceptible to TF-targeted treatment and may offer new opportunity in cancer patients.