| Literature DB >> 30768955 |
Katsuya Nagaoka1, Xuewei Bai2, Kosuke Ogawa1, Xiaoqun Dong3, Songhua Zhang1, Yanmei Zhou4, Rolf I Carlson1, Zhi-Gang Jiang5, Steve Fuller5, Michael S Lebowitz5, Hossein Ghanbari5, Jack R Wands6.
Abstract
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.Entities:
Keywords: ADC; ASPH; Cytotoxicity; Pancreatic cancer; Pulmonary metastasis
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Year: 2019 PMID： 30768955 PMCID： PMC6411448 DOI： 10.1016/j.canlet.2019.02.006
Source DB: PubMed Journal: Cancer Lett ISSN： 0304-3835 Impact factor: 8.679