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

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 (89)Zr-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 (89)Zr. 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 (89)Zr-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. (89)Zr labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of (89)Zr-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 (89)Zr-Df-cetuximab, and ex-vivo histology all confirmed the in vivo target specificity of (89)Zr-Df-TRC105.

CONCLUSION:

We report here the first successful PET imaging of CD105 expression with (89)Zr as the radiolabel. Rapid, persistent, CD105-specific uptake of (89)Zr-Df-TRC105 in the 4T1 tumor was observed.

• Authors: 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 (Affiliation: Department of Radiology, University of Wisconsin-Madison, Madison, WI 53705, USA.)
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 39 Issue 1 Pg. 138-48 (Jan 2012) ISSN: 1619-7089 [Electronic] Germany
• PMID: 21909753 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 4-isothiocyanatobenzyl-desferrioxamine
• Antibodies, Monoclonal
• Antigens, CD
• ENG protein, human
• Isothiocyanates
• Radioisotopes
• Receptors, Cell Surface
• Deferoxamine
• Zirconium

Topics

• Animals
• Antibodies, Monoclonal (chemistry, diagnostic use, pharmacokinetics)
• Antigens, CD (metabolism)
• Cell Line, Tumor
• Deferoxamine (analogs & derivatives, chemistry)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Isothiocyanates (chemistry)
• Mice
• Positron-Emission Tomography (methods)
• Radioisotopes (diagnostic use)
• Receptors, Cell Surface (metabolism)
• Zirconium (diagnostic use)