Granzyme B-based cytolytic fusion protein targeting EpCAM specifically kills triple negative breast cancer cells in vitro and inhibits tumor growth in a subcutaneous mouse tumor model

Cancer Letters
Manal AmouryS Barth

Abstract

Triple-negative breast cancer (TNBC) is associated with poor prognosis and high prevalence among young premenopausal women. Unlike in other breast cancer subtypes, no targeted therapy is currently available. Overexpression of epithelial cell adhesion molecule (EpCAM) in 60% of TNBC tumors correlates with poorer prognosis and is associated with cancer stem cell phenotype. Thus, selective elimination of EpCAM(+) TNBC tumor cells is of clinical importance. Therefore, we constructed a fully human targeted cytolytic fusion protein, designated GbR201K-αEpCAM(scFv), in which an EpCAM-selective single-chain antibody fragment (scFv) is genetically fused to a granzyme B (Gb) mutant with reduced sensitivity to its natural inhibitor serpin B9. In vitro studies confirmed its specific binding, internalization and cytotoxicity toward a panel of EpCAM-expressing TNBC cells. Biodistribution kinetics and tumor-targeting efficacy using MDA-MB-468 cells in a human TNBC xenograft model in mice revealed selective accumulation of GbR201K-αEpCAM(scFv) in the tumors after i.v. injection. Moreover, treatment of tumor-bearing mice demonstrated a prominent inhibition of tumor growth of up to 50 % in this proof-of-concept study. Taken together, our results...Continue Reading

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Citations

Jul 18, 2017·Biomedicines·Khalid A Mohamedali, Michael G Rosenblum
Jul 25, 2019·Journal of Biochemical and Molecular Toxicology·Oguzhan TatarIbrahim Hanifi Ozercan
Aug 31, 2019·Artificial Cells, Nanomedicine, and Biotechnology·Xuhong ZhaoShengsong Tang
Dec 4, 2019·Journal of Drug Targeting·Mehwish Saba Aslam, Liudi Yuan
Mar 30, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Dandan ZhangXuesong Yang
Jan 19, 2018·Oncology Letters·Yu WangZhitu Zhu
Jun 22, 2018·Biomedicines·Precious HlongwaneStefan Barth
Aug 1, 2019·Journal of Experimental & Clinical Cancer Research : CR·Lawrence H CheungMichael G Rosenblum
Apr 3, 2019·Molecular Biology Reports·Nafiseh PaydarniaSaeed Ranjbar
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Jul 4, 2018·Molecular Cancer Therapeutics·Anke E M van ErpEmmy D G Fleuren
Nov 16, 2017·The American Journal of Pathology·Evelyn JiaggeLisa A Newman

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