Back to Search
Start Over
Pathological expression of tissue factor confers promising antitumor response to a novel therapeutic antibody SC1 in triple negative breast cancer and pancreatic adenocarcinoma
- Source :
- Oncotarget
- Publication Year :
- 2017
- Publisher :
- Impact Journals LLC, 2017.
-
Abstract
- // Xuesai Zhang 1 , Qingrou Li 1 , Hui Zhao 1 , Lanping Ma 2 , Tao Meng 2 , Jianchang Qian 1 , Rui Jin 1 , Jingkang Shen 2 and Ker Yu 1 1 Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China 2 Department 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 (EC 50 : 0.019 nM), TF-positive TNBC- or PaC cells (EC 50 : 2.5 nM), intracellular protease activated receptor 2 (PAR2) signaling (IC 50 : 2-3 nM) and tumor-initiated coagulation (IC 50 : 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.
- Subjects :
- 0301 basic medicine
Pathology
medicine.medical_specialty
Antibody-drug conjugate
Vimentin
Malignancy
Metastasis
antibody-drug conjugate
03 medical and health sciences
Tissue factor
0302 clinical medicine
pancreatic adenocarcinoma
Medicine
metastasis
Triple-negative breast cancer
biology
business.industry
medicine.disease
tissue factor
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
triple negative breast cancer
Cancer cell
Cancer research
biology.protein
Adenocarcinoma
business
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Volume :
- 8
- Issue :
- 35
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....d25e0d373bdc2eb3697efecf91a83f8d