Anti-tumor activity of antibody drug conjugate targeting aspartate-β-hydroxylase in pancreatic ductal adenocarcinoma
| Autor: | Songhua Zhang, Jack R. Wands, Steve Fuller, Zhi-Gang Jiang, Katsuya Nagaoka, Xuewei Bai, Kosuke Ogawa, Rolf I. Carlson, Hossein A. Ghanbari, Yanmei Zhou, Xiaoqun Dong, Michael S. Lebowitz |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Antibody-drug conjugate Immunoconjugates Lung Neoplasms endocrine system diseases medicine.drug_class Cell Survival Muscle Proteins Monoclonal antibody Article Mixed Function Oxygenases 03 medical and health sciences Mice 0302 clinical medicine Pancreatic cancer Cell Line Tumor medicine Animals Humans Cytotoxicity Cell Proliferation biology Chemistry Cell growth Calcium-Binding Proteins Membrane Proteins medicine.disease Xenograft Model Antitumor Assays digestive system diseases ASPH Up-Regulation body regions Gene Expression Regulation Neoplastic Pancreatic Neoplasms 030104 developmental biology Oncology Apoptosis 030220 oncology & carcinogenesis Cancer research biology.protein Immunohistochemistry Administration Intravenous Carcinoma Pancreatic Ductal |
| Zdroj: | Cancer Lett |
| ISSN: | 1872-7980 |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with very limited treatment options. Antibody drug conjugates (ADCs) are promising cytotoxic agents capable of highly selective delivery. Aspartate-β-hydroxylase (ASPH) is a type II transmembrane protein highly expressed in PDACs (97.1%) but not normal pancreas. We investigated anti-tumor effects of an ADC guided by a human monoclonal antibody (SNS-622) against ASPH in human PDAC cell lines and derived subcutaneous (s.c.) xenograft as well as a patient-derived xenograft (PDX) murine model with spontaneous pulmonary metastasis. The cytotoxic effects exhibited by several candidate payloads linked to SNS-622 antibody targeting ASPH(+) PDACs were analyzed. After i.v. administration of SNS-622-emtansine (DM1) ADC, the primary PDAC tumor growth and progression (number and size of pulmonary metastases) were determined. The PDAC cell lines, s.c. and PDX tumors treated with ADC were tested for cell proliferation, cytotoxicity and apoptosis by MTS and immunohistochemistry (IHC) assays. SNS-622-DM1 construct has demonstrated optimal anti-tumor effects in vitro. In the PDX model of human PDAC, SNS-622-DM1 ADC exerted substantially inhibitory effects on tumor growth and pulmonary metastasis through attenuating proliferation and promoting apoptosis. |
| Databáze: | OpenAIRE |
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