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

Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14181-14190. doi: 10.1073/pnas.1817442116. Epub 2019 May 8.

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.

Keywords: ECM; PET imaging; cancer; fibrosis; nanobodies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / diagnostic imaging
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics*
  • Carcinoma, Pancreatic Ductal / diagnostic imaging*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Extracellular Matrix / drug effects*
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / pathology
  • Female
  • Fibrosis / pathology
  • Humans
  • Male
  • Mice
  • Pancreatic Neoplasms / diagnostic imaging*
  • Pancreatic Neoplasms / pathology
  • Positron Emission Tomography Computed Tomography
  • Prostatic Neoplasms / diagnostic imaging
  • Prostatic Neoplasms / pathology
  • Radiopharmaceuticals / pharmacology
  • Single-Domain Antibodies / chemistry
  • Single-Domain Antibodies / pharmacology

Substances

  • Radiopharmaceuticals
  • Single-Domain Antibodies

Supplementary concepts

  • Pancreatic Carcinoma