Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 28, Pages 14181-14190Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1817442116
Keywords
cancer; ECM; nanobodies; PET imaging; fibrosis
Categories
Funding
- Mazumdar-Shaw International Oncology Fellowship
- Massachusetts Institute of Technology Ludwig Center for Molecular Oncology Research postdoctoral fellowship
- Howard Hughes Medical Institute
- Department of Defense Breast Cancer Research Program Investigator Award [W81XWH-14-1-0240]
- National Cancer Institute [P30CA14051-45S1]
- Lustgarten Foundation, Inc.
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Extracellular matrix (ECM) deposition is a hallmark of many diseases, including cancer and fibroses. To exploit the ECM as an imaging and therapeutic target, we developed alpaca-derived libraries of nanobodies against disease-associated ECM proteins. We describe here one such nanobody, NJB2, specific for an alternatively spliced domain of fibronectin expressed in disease ECM and neovasculature. We showed by noninvasive in vivo immuno-PET/CT imaging that NJB2 detects primary tumors and metastatic sites with excellent specificity in multiple models of breast cancer, including human and mouse triple-negative breast cancer, and in melanoma. We also imaged mice with pancreatic ductal adenocarcinoma (PDAC) in which NJB2 was able to detect not only PDAC tumors but also early pancreatic lesions called pancreatic intraepithelial neoplasias, which are challenging to detect by any current imaging modalities, with excellent clarity and signal-to-noise ratios that outperformed conventional 2-fluorodeoxyglucose PET/CT imaging. NJB2 also detected pulmonary fibrosis in a bleomycin-induced fibrosis model. We propose NJB2 and similar anti-ECM nanobodies as powerful tools for noninvasive detection of tumors, metastatic lesions, and fibroses. Furthermore, the selective recognition of disease tissues makes NJB2 a promising candidate for nanobody-based therapeutic applications.
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