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Noninvasive imaging of tumor progression, metastasis, and fibrosis using a nanobody targeting the extracellular matrix.

ABSTRACT: 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.

SUBMITTER: Jailkhani N

PROVIDER: S-EPMC6628802 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Noninvasive imaging of tumor progression, metastasis, and fibrosis using a nanobody targeting the extracellular matrix.

Jailkhani Noor N Ingram Jessica R JR Rashidian Mohammad M Rickelt Steffen S Tian Chenxi C Mak Howard H Jiang Zhigang Z Ploegh Hidde L HL Hynes Richard O RO

Proceedings of the National Academy of Sciences of the United States of America 20190508 28

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 metastat ...[more]

PMID: 31068469

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Project description:In a variety of diseases, from benign to life-threatening ones, inflammation plays a major role. Monitoring the intensity and extent of a multifaceted inflammatory process has become a cornerstone in diagnostics and therapy monitoring. However, the current tools lack the ability to provide insight into one of its most crucial aspects, namely, the alteration of the extracellular matrix (ECM). Using a radiolabeled platelet glycoprotein VI-based ECM-targeting fusion protein (GPVI-Fc), we investigated how binding of GPVI-Fc on fibrous tissue could uncover the progression of several inflammatory disease models at different stages (rheumatoid arthritis, cutaneous delayed-type hypersensitivity, lung inflammation and experimental autoimmune encephalomyelitis). Methods: The fusion protein GPVI-Fc was covalently linked to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and subsequently labeled with 64Cu. We analyzed noninvasively in vivo 64Cu-GPVI-Fc accumulation in murine cutaneous delayed-type hypersensitivity, anti-glucose-6-phosphate isomerase serum-induced rheumatoid arthritis, lipopolysaccharide-induced lung inflammation and an experimental autoimmune encephalomyelitis model. Static and dynamic Positron Emission Tomography (PET) of the radiotracer distribution was performed in vivo, with ex vivo autoradiography confirmation, yielding quantitative accumulation and a distribution map of 64Cu-GPVI-Fc. Ex vivo tissue histological staining was performed on harvested samples to highlight the fusion protein binding to collagen I, II and III, fibronectin and fibrinogen as well as the morphology of excised tissue. Results: 64Cu-GPVI-Fc showed a several-fold increased uptake in inflamed tissue compared to control tissue, particularly in the RA model, with a peak 24 h after radiotracer injection of up to half the injected dose. Blocking and isotype control experiments indicated a target-driven accumulation of the radiotracer in the case of chronic inflammation. Histological analysis confirmed a prolonged accumulation at the inflammation site, with a pronounced colocalization with the different components of the ECM (collagen III and fibronectin notably). Binding of the fusion protein appeared to be specific to the ECM but unspecific to particular components. Conclusion: Imaging of 64Cu-GPVI-Fc accumulation in the ECM matrix appears to be a promising candidate for monitoring chronic inflammation. By binding to exposed fibrous tissue (collagen, fibronectin, etc.) after extravasation, a new insight is provided into the fibrotic events resulting from a prolonged inflammatory state.

Dataset Information

Noninvasive imaging of tumor progression, metastasis, and fibrosis using a nanobody targeting the extracellular matrix.

Publications

Noninvasive imaging of tumor progression, metastasis, and fibrosis using a nanobody targeting the extracellular matrix.

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