Positron emission tomography imaging of CD105 expression during tumor angiogenesis

  • Hao Hong
  • Yunan Yang
  • Yin Zhang
  • Jonathan W. Engle
  • Todd E. Barnhart
  • Robert J. Nickles
  • Bryan R. Leigh
  • Weibo Cai
Original Article

Abstract

Purpose

Overexpression of CD105 (endoglin) correlates with poor prognosis in many solid tumor types. Tumor microvessel density (MVD) assessed by CD105 staining is the current gold standard for evaluating tumor angiogenesis in the clinic. The goal of this study was to develop a positron emission tomography (PET) tracer for imaging CD105 expression.

Methods

TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with 64Cu. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and DOTA-TRC105. PET imaging, biodistribution, blocking, and ex vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 64Cu-DOTA-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control.

Results

FACS analysis of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and DOTA-TRC105, which was further validated by fluorescence microscopy. 64Cu labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of the tracer was 8.0 ± 0.5, 10.4 ± 2.8, and 9.7 ± 1.8%ID/g at 4, 24, and 48 h post-injection, respectively (n = 3), higher than most organs at late time points which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with 64Cu-DOTA-cetuximab, as well as ex vivo histology all confirmed the in vivo target specificity of 64Cu-DOTA-TRC105.

Conclusion

This is the first successful PET imaging study of CD105 expression. Fast, prominent, persistent, and CD105-specific uptake of the tracer in the 4T1 tumor was observed. Further studies are warranted and currently underway.

Keywords

CD105/Endoglin Positron emission tomography (PET) Tumor angiogenesis 64Cu RadioimmunoPET TRC105 

Notes

Acknowledgements

This work is supported, in part, by the Wisconsin Partnership Program, the University of Wisconsin Carbone Cancer Center, NCRR 1UL1RR025011, a Susan G. Komen Postdoctoral Fellowship (to H. Hong), and a DOD PCRP IDEA Award.

Conflicts of interest

BRL is an employee of TRACON Pharmaceuticals, Inc. The other authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Hao Hong
    • 1
  • Yunan Yang
    • 1
    • 5
  • Yin Zhang
    • 2
  • Jonathan W. Engle
    • 2
  • Todd E. Barnhart
    • 2
  • Robert J. Nickles
    • 2
  • Bryan R. Leigh
    • 3
  • Weibo Cai
    • 1
    • 2
    • 4
    • 6
  1. 1.Department of RadiologyUniversity of Wisconsin - MadisonMadisonUSA
  2. 2.Department of Medical PhysicsUniversity of Wisconsin - MadisonMadisonUSA
  3. 3.TRACON Pharmaceuticals, Inc.San DiegoUSA
  4. 4.University of Wisconsin Carbone Cancer CenterMadisonUSA
  5. 5.Department of Ultrasound, Xinqiao HospitalThird Military Medical UniversityChongqingPeople’s Republic of China
  6. 6.Departments of Radiology and Medical Physics, School of Medicine and Public HealthUniversity of Wisconsin - MadisonMadisonUSA

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