Oncotarget

Research Papers:

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

Xuesai Zhang, Qingrou Li, Hui Zhao, Lanping Ma, Tao Meng, Jianchang Qian, Rui Jin, Jingkang Shen and Ker Yu _

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Oncotarget. 2017; 8:59086-59102. https://doi.org/10.18632/oncotarget.19175

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Abstract

Xuesai Zhang1, Qingrou Li1, Hui Zhao1, Lanping Ma2, Tao Meng2, Jianchang Qian1, Rui Jin1, Jingkang Shen2 and Ker Yu1

1Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China

2Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

Correspondence to:

Ker Yu, email: keryu@fudan.edu.cn

Keywords: tissue factor, triple negative breast cancer, pancreatic adenocarcinoma, metastasis, antibody-drug conjugate

Received: March 06, 2017    Accepted: June 05, 2017    Published: July 10, 2017

ABSTRACT

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 (EC50: 0.019 nM), TF-positive TNBC- or PaC cells (EC50: 2.5 nM), intracellular protease activated receptor 2 (PAR2) signaling (IC50: 2-3 nM) and tumor-initiated coagulation (IC50: <10 nM). Depletion of TF or SC1-treatment in TNBC or PaC cells inhibited TF-induced cell migration, lung metastasis and tumor growth in vivo, accompanied by diminished levels of tumor angiogenesis and stromal fibrosis. We further propose TF as a promising target for antibody-drug conjugate (ADC) development based on its rapid and efficient internalization of SC1-drug conjugate. Both SC1-DM1 and SC1-MMAE elicited exquisite cytotoxicity in TF-positive TNBC and PaC cells (IC50: 0.02-0.1 nM) but not in TF-negative cells (>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.


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