Positron emission tomography imaging of CD105 expression with 89Zr-Df-TRC105

Hao Hong, Gregory W. Severin, Yunan Yang, Jonathan W. Engle, Yin Zhang, Todd E. Barnhart, Glenn Liu, Bryan R. Leigh, Robert J. Nickles, Weibo Cai

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Purpose: High tumor microvessel density correlates with a poor prognosis in multiple solid tumor types. The clinical gold standard for assessing microvessel density is CD105 immunohistochemistry on paraffin-embedded tumor specimens. The goal of this study was to develop an 89Zr-based PET tracer for noninvasive imaging of CD105 expression.
Methods: TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to p-isothiocyanatobenzyl- desferrioxamine (Df-Bz-NCS) and labeled with 89Zr. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and Df-TRC105. PET imaging, biodistribution, blocking, and ex-vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the pharmacokinetics and tumor-targeting of 89Zr-Df-TRC105. Another chimeric antibody, cetuximab, was used as an isotype-matched control.
Results: FACS analysis of HUVECs revealed no difference in CD105 binding affinity between TRC105 and Df- TRC105, which was further validated by fluorescence microscopy. 89Zr labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of 89Zr-Df-TRC105 was 6.1±1.2, 14.3±1.2, 12.4±1.5, 7.1±0.9, and 5.2±0.3%ID/g at 5, 24, 48, 72, and 96 h after injection, respectively (n=4), higher than all organs starting from 24 h after injection, which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with 89Zr-Df-cetuximab, and ex-vivo histology all confirmed the in vivo target specificity of 89Zr-Df- TRC105.
Conclusion: We report here the first successful PET imaging of CD105 expression with 89Zr as the radiolabel. Rapid, persistent, CD105-specific uptake of 89Zr-Df-TRC105 in the 4T1 tumor was observed. © Springer-Verlag 2011.
Original languageEnglish
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume39
Issue number1
Pages (from-to)138-148
Number of pages11
ISSN1619-7070
DOIs
Publication statusPublished - 2012
Externally publishedYes

Keywords

  • Radiology, Nuclear Medicine and Imaging
  • 89Zr
  • CD105/endoglin
  • Positron emission tomography (PET)
  • RadioimmunoPET
  • TRC105
  • Tumor angiogenesis
  • antineoplastic agent
  • cetuximab
  • chimeric antibody
  • deferoxamine
  • endoglin
  • monoclonal antibody
  • tracer
  • trc 105
  • unclassified drug
  • zirconium
  • 4 isothiocyanatobenzyl desferrioxamine
  • 4-isothiocyanatobenzyl-desferrioxamine
  • cell surface receptor
  • diagnostic agent
  • drug derivative
  • ENG protein, human
  • isothiocyanic acid derivative
  • leukocyte antigen
  • radioisotope
  • animal cell
  • animal experiment
  • animal model
  • article
  • binding affinity
  • breast tumor
  • controlled study
  • drug specificity
  • ex vivo study
  • female
  • fluorescence activated cell sorting
  • fluorescence microscopy
  • histopathology
  • human
  • human cell
  • in vivo study
  • information processing
  • isotope labeling
  • mouse
  • non invasive procedure
  • nonhuman
  • positron emission tomography
  • protein binding
  • protein expression
  • umbilical vein endothelial cell
  • validation process
  • animal
  • chemistry
  • gene expression regulation
  • metabolism
  • methodology
  • tumor cell line
  • Animals
  • Antibodies, Monoclonal
  • Antigens, CD
  • Cell Line, Tumor
  • Deferoxamine
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Isothiocyanates
  • Mice
  • Positron-Emission Tomography
  • Radioisotopes
  • Receptors, Cell Surface
  • Zirconium
  • C6V6S92N3C Zirconium
  • J06Y7MXW4D Deferoxamine

Cite this

Hong, H., Severin, G. W., Yang, Y., Engle, J. W., Zhang, Y., Barnhart, T. E., Liu, G., Leigh, B. R., Nickles, R. J., & Cai, W. (2012). Positron emission tomography imaging of CD105 expression with 89Zr-Df-TRC105. European Journal of Nuclear Medicine and Molecular Imaging, 39(1), 138-148. https://doi.org/10.1007/s00259-011-1930-x