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Oncotarget. 2017 Jul 4;8(27):44605-44624. doi: 10.18632/oncotarget.17883.

The collagen receptor uPARAP/Endo180 as a novel target for antibody-drug conjugate mediated treatment of mesenchymal and leukemic cancers.

Author information

1
The Finsen Laboratory, Rigshospitalet, Biotech Research and Innovation Center (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
2
Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, USA.
3
Experimental Animal Models Section, Department of Veterinary Disease Biology, University of Copenhagen, DK-1871 Frederiksberg C, Denmark.
4
Danish Cancer Society Research Center, DK-2100 Copenhagen Ø, Denmark.

Abstract

A key task in developing the field of personalized cancer therapy is the identification of novel molecular targets that enable treatment of cancers not susceptible to other means of specific therapy. The collagen receptor uPARAP/Endo180 is overexpressed by malignant cells in several non-epithelial cancers, notably including sarcomas, glioblastomas and subsets of acute myeloid leukemia. In contrast, in healthy adult individuals, expression is restricted to minor subsets of mesenchymal cells. Functionally, uPARAP/Endo180 is a rapidly recycling endocytic receptor that delivers its cargo directly into the endosomal-lysosomal system, thus opening a potential route of entry into receptor-positive cells. This combination of specific expression and endocytic function appears well suited for targeting of uPARAP/Endo180-positive cancers by antibody-drug conjugate (ADC) mediated drug delivery. Therefore, we utilized a specific monoclonal antibody against uPARAP/Endo180, raised through immunization of a uPARAP/Endo180 knock-out mouse, which reacts with both the human and the murine receptor, to construct a uPARAP-directed ADC. This antibody was coupled to the highly toxic dolastatin derivative, monomethyl auristatin E, via a cathepsin-labile valine-citrulline linker. With this ADC, we show strong and receptor-dependent cytotoxicity in vitro in uPARAP/Endo180-positive cancer cell lines of sarcoma, glioblastoma and leukemic origin. Furthermore, we demonstrate the potency of the ADC in vivo in a xenograft mouse model with human uPARAP/Endo180-positive leukemic cells, obtaining a complete cure of all tested mice following intravenous ADC treatment with no sign of adverse effects. Our study identifies uPARAP/Endo180 as a promising target for novel therapy against several highly malignant cancer types.

KEYWORDS:

antibody-drug conjugate; glioblastoma; leukemia; sarcoma; uPARAP

PMID:
28574834
PMCID:
PMC5546505
DOI:
10.18632/oncotarget.17883
[Indexed for MEDLINE]
Free PMC Article

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