Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer

Haiming Luo; Christopher G England; Sixiang Shi; Stephen A Graves; Reinier Hernandez; Bai Liu; Charles P Theuer; Hing C Wong; Robert J Nickles; Weibo Cai

doi:10.1158/1078-0432.CCR-15-2054

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Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer

Journal article

Open access

Peer reviewed

Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer

Haiming Luo, Christopher G England, Sixiang Shi, Stephen A Graves, Reinier Hernandez, Bai Liu, Charles P Theuer, Hing C Wong, Robert J Nickles and Weibo Cai

Clinical cancer research, Vol.22(15), pp.3821-3830

08/01/2016

DOI: 10.1158/1078-0432.CCR-15-2054

PMCID: PMC4970931

PMID: 27026197

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https://doi.org/10.1158/1078-0432.CCR-15-2054View

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Abstract

Pancreatic adenocarcinoma is a highly aggressive cancer, currently treated with limited success and dismal outcomes. New diagnostic and treatment strategies offer the potential to reduce cancer mortality. Developing highly specific noninvasive imaging probes for pancreatic cancer is essential to improving diagnostic accuracy and monitoring therapeutic intervention. A bispecific heterodimer was synthesized by conjugating an anti-tissue factor (TF) Fab with an anti-CD105 Fab, via the bio-orthogonal "click" reaction between tetrazine (Tz) and trans-cyclooctene (TCO). The heterodimer was labeled with (64)Cu for PET imaging of nude mice bearing BXPC-3 xenograft and orthotopic pancreatic tumors. PET imaging of BXPC-3 (TF/CD105(+/+)) xenograft tumors with (64)Cu-labeled heterodimer displayed significantly enhanced tumor uptake (28.8 ± 3.2 %ID/g; n = 4; SD) at 30 hours postinjection, as compared with each of their monospecific Fab tracers (12.5 ± 1.4 and 7.1 ± 2.6 %ID/g; n = 3; SD). In addition, the activity-concentration ratio allowed for effective tumor visualization (tumor/muscle ratio 75.2 ± 9.4 at 30 hours postinjection.; n = 4; SD). Furthermore, (64)Cu-NOTA-heterodimer enabled sensitive detection of orthotopic pancreatic tumor lesions with an uptake of 17.1 ± 4.9 %ID/g at 30 hours postinjection and tumor/muscle ratio of 72.3 ± 46.7. This study demonstrates that dual targeting of TF and CD105 provided synergistic improvements in binding affinity and tumor localization of the heterodimer. Dual-targeted imaging agents of pancreatic and other cancers may assist in diagnosing pancreatic malignancies as well as reliable monitoring of therapeutic response. Clin Cancer Res; 22(15); 3821-30. ©2016 AACR.

Animals

Biomarkers

Cell Line, Tumor

Disease Models, Animal

Female

Flow Cytometry

Humans

Immunoglobulin Fab Fragments - chemistry

Immunoglobulin Fab Fragments - metabolism

Mice

Neprilysin - metabolism

Pancreatic Neoplasms - diagnostic imaging

Pancreatic Neoplasms - metabolism

Pancreatic Neoplasms - pathology

Positron-Emission Tomography - methods

Protein Multimerization

Radiopharmaceuticals

Thromboplastin - metabolism

Tissue Distribution

Details

Title: Subtitle: Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer
Creators: Haiming Luo - University of Wisconsin–Madison
Christopher G England - University of Wisconsin–Madison
Sixiang Shi - University of Wisconsin–Madison
Stephen A Graves - University of Wisconsin–Madison
Reinier Hernandez - University of Wisconsin–Madison
Bai Liu - Altor BioScience (United States)
Charles P Theuer - Tracon Pharmaceuticals (United States)
Hing C Wong - Altor BioScience (United States)
Robert J Nickles - University of Wisconsin–Madison
Weibo Cai - University of Wisconsin–Madison
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.22(15), pp.3821-3830
DOI: 10.1158/1078-0432.CCR-15-2054
PMID: 27026197
PMCID: PMC4970931
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Grant note: T32 GM008349 / NIGMS NIH HHS T32 CA009206 / NCI NIH HHS R01 CA169365 / NCI NIH HHS P30 CA014520 / NCI NIH HHS
Language: English
Date published: 08/01/2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Radiation Oncology
Record Identifier: 9984383917102771

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