Oncotarget

Research Papers:

Antibody-based PET of uPA/uPAR signaling with broad applicability for cancer imaging

Dongzhi Yang, Gregory W. Severin, Casey A. Dougherty, Rachel Lombardi, Daiqin Chen, Marcian E. Van Dort, Todd E. Barnhart, Brian D. Ross, Andrew P. Mazar and Hao Hong _

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Oncotarget. 2016; 7:73912-73924. https://doi.org/10.18632/oncotarget.12528

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Abstract

Dongzhi Yang1,2,*, Gregory W. Severin3,4,*, Casey A. Dougherty1,5, Rachel Lombardi1, Daiqin Chen1, Marcian E. Van Dort1, Todd E. Barnhart6, Brian D. Ross1, Andrew P. Mazar7, Hao Hong1

1Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan 48109, United States

2Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China

3Center for Nuclear Technologies, Technical University of Denmark, 4000 Roskilde, Denmark

4Department of Chemistry, Facility for Rare Isotope Beams, Michigan State University, East Lansing, Michigan 48824, United States

5Department of Chemistry, Iona College, New Rochelle, New York 10801, United States

6Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States

7Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States

*These authors contributed equally to this work

Correspondence to:

Andrew P. Mazar, email: [email protected]

Hao Hong, email: [email protected]

Keywords: urokinase plasminogen activator (uPA), uPAR, immunoPET, quantitative analysis, cancer biomarkers

Received: July 13, 2016     Accepted: October 03, 2016     Published: October 08, 2016

ABSTRACT

Mounting evidence suggests that the urokinase plasminogen activator (uPA) and its receptor (uPAR) play a central role in tumor progression. The goal of this study was to develop an 89Zr-labeled, antibody-based positron emission tomography (PET) tracer for quantitative imaging of the uPA/uPAR system. An anti-uPA monoclonal antibody (ATN-291) was conjugated with a deferoxamine (Df) derivative and subsequently labeled with 89Zr. Flow cytometry, microscopy studies, and competitive binding assays were conducted to validate the binding specificity of Df-ATN-291 against uPA. PET imaging with 89Zr-Df-ATN-291 was carried out in different tumors with distinct expression levels of uPA. Biodistribution, histology examination, and Western blotting were performed to correlate tumor uptake with uPA or uPAR expression. ATN-291 retained uPA binding affinity and specificity after Df conjugation. 89Zr-labeling of ATN-291 was achieved in good radiochemical yield and high specific activity. Serial PET imaging demonstrated that, in most tumors studied (except uPA- LNCaP), the uptake of 89Zr-Df-ATN-291 was higher compared to major organs at 120 h post-injection, providing excellent tumor contrast. The tumor-to-muscle ratio of 89Zr-Df-ATN-291 in U87MG was as high as 45.2 ± 9.0 at 120 h p.i. In vivo uPA specificity of 89Zr-Df-ATN-291 was confirmed by successful pharmacological blocking of tumor uptake with ATN-291 in U87MG tumors. Although the detailed mechanisms behind in vivo 89Zr-Df-ATN-291 tumor uptake remained to be further elucidated, quantitative PET imaging with 89Zr-Df-ATN-291 in tumors can facilitate oncologists to adopt more relevant cancer treatment planning.


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