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

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

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.

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References

  1. Wu AM. Antibodies and antimatter: the resurgence of immuno-PET. J Nucl Med. 2009;50:2–5.

    Article  PubMed  CAS  Google Scholar 

  2. van Dongen GA, Vosjan MJ. Immuno-positron emission tomography: shedding light on clinical antibody therapy. Cancer Biother Radiopharm. 2010;25:375–85.

    Article  PubMed  Google Scholar 

  3. Zhang Y, Hong H, Cai W. PET tracers based on zirconium-89. Curr Radiopharm 2011;4:131–9

    Article  Google Scholar 

  4. Dijkers EC, Oude Munnink TH, Kosterink JG, Brouwers AH, Jager PL, de Jong JR, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87:586–92.

    Article  PubMed  CAS  Google Scholar 

  5. Cai W, Chen X. Multimodality molecular imaging of tumor angiogenesis. J Nucl Med. 2008;49 Suppl 2:113S–28S.

    Article  PubMed  CAS  Google Scholar 

  6. Cai W, Chen X. Multimodality imaging of vascular endothelial growth factor and vascular endothelial growth factor receptor expression. Front Biosci. 2007;12:4267–79.

    Article  PubMed  CAS  Google Scholar 

  7. Cai W, Niu G, Chen X. Imaging of integrins as biomarkers for tumor angiogenesis. Curr Pharm Des. 2008;14:2943–73.

    Article  PubMed  CAS  Google Scholar 

  8. Dijkgraaf I, Boerman OC. Radionuclide imaging of tumor angiogenesis. Cancer Biother Radiopharm. 2009;24:637–47.

    Article  PubMed  CAS  Google Scholar 

  9. Dallas NA, Samuel S, Xia L, Fan F, Gray MJ, Lim SJ, et al. Endoglin (CD105): a marker of tumor vasculature and potential target for therapy. Clin Cancer Res. 2008;14:1931–7.

    Article  PubMed  CAS  Google Scholar 

  10. Fonsatti E, Nicolay HJ, Altomonte M, Covre A, Maio M. Targeting cancer vasculature via endoglin/CD105: a novel antibody-based diagnostic and therapeutic strategy in solid tumours. Cardiovasc Res. 2010;86:12–9.

    Article  PubMed  CAS  Google Scholar 

  11. Seon BK, Haba A, Matsuno F, Takahashi N, Tsujie M, She X, et al. Endoglin-targeted cancer therapy. Curr Drug Deliv. 2011;8:135–43.

    Article  PubMed  CAS  Google Scholar 

  12. Cai W, Rao J, Gambhir SS, Chen X. How molecular imaging is speeding up antiangiogenic drug development. Mol Cancer Ther. 2006;5:2624–33.

    Article  PubMed  CAS  Google Scholar 

  13. Zhang Y, Yang Y, Hong H, Cai W. Multimodality molecular imaging of CD105 (Endoglin) expression. Int J Clin Exp Med. 2011;4:32–42.

    PubMed  Google Scholar 

  14. Zhang D, Feng XY, Henning TD, Wen L, Lu WY, Pan H, et al. MR imaging of tumor angiogenesis using sterically stabilized Gd-DTPA liposomes targeted to CD105. Eur J Radiol. 2009;70:180–9.

    Article  PubMed  Google Scholar 

  15. Bredow S, Lewin M, Hofmann B, Marecos E, Weissleder R. Imaging of tumour neovasculature by targeting the TGF-beta binding receptor endoglin. Eur J Cancer. 2000;36:675–81.

    Article  PubMed  CAS  Google Scholar 

  16. Costello B, Li C, Duff S, Butterworth D, Khan A, Perkins M, et al. Perfusion of 99mTc-labeled CD105 Mab into kidneys from patients with renal carcinoma suggests that CD105 is a promising vascular target. Int J Cancer. 2004;109:436–41.

    Article  PubMed  CAS  Google Scholar 

  17. Fonsatti E, Jekunen AP, Kairemo KJ, Coral S, Snellman M, Nicotra MR, et al. Endoglin is a suitable target for efficient imaging of solid tumors: in vivo evidence in a canine mammary carcinoma model. Clin Cancer Res. 2000;6:2037–43.

    PubMed  CAS  Google Scholar 

  18. Korpanty G, Carbon JG, Grayburn PA, Fleming JB, Brekken RA. Monitoring response to anticancer therapy by targeting microbubbles to tumor vasculature. Clin Cancer Res. 2007;13:323–30.

    Article  PubMed  CAS  Google Scholar 

  19. Korpanty G, Grayburn PA, Shohet RV, Brekken RA. Targeting vascular endothelium with avidin microbubbles. Ultrasound Med Biol. 2005;31:1279–83.

    Article  PubMed  Google Scholar 

  20. Cui S, Lu SZ, Chen YD, He GX, Liu JP, Song ZY, et al. Relationship between intravascular ultrasound imaging features of coronary plaques and soluble CD105 level in patients with coronary heart disease. Chin Med J Engl. 2007;120:595–7.

    PubMed  Google Scholar 

  21. Hong H, Yang Y, Zhang Y, Engle JW, Barnhart TE, Nickles RJ, et al. Positron emission tomography imaging of CD105 expression during tumor angiogenesis. Eur J Nucl Med Mol Imaging. 2011;38:1335–43.

    Article  PubMed  CAS  Google Scholar 

  22. Yang Y, Zhang Y, Hong H, Liu G, Leigh B, Cai W. In vivo near-infrared fluorescence imaging of CD105 expression during tumor angiogenesis. Eur J Nucl Med Mol Imaging. 2011. doi:10.1007/s00259-011-1886-x

  23. Lee SY, Hong YD, Felipe PM, Pyun MS, Choi SJ. Radiolabeling of monoclonal anti-CD105 with 177Lu for potential use in radioimmunotherapy. Appl Radiat Isot. 2009;67:1366–9.

    Article  PubMed  CAS  Google Scholar 

  24. Mendelson DS, Gordon MS, Rosen LS, Hurwitz H, Wong MK, Adams BJ, et al. Phase I study of TRC105 (anti-CD105 [endoglin] antibody) therapy in patients with advanced refractory cancer. J Clin Oncol. 2010;28:15s.

    Google Scholar 

  25. Meijs WE, Herscheid JDM, Haisma HJ, Pinedo HM. Evaluation of desferal as a bifunctional chelating agent for labeling antibodies with Zr-89. Int J Rad Appl Instrum A. 1992;43:1443–7.

    Article  PubMed  CAS  Google Scholar 

  26. Vosjan MJ, Perk LR, Visser GW, Budde M, Jurek P, Kiefer GE, et al. Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine. Nat Protoc. 2010;5:739–43.

    Article  PubMed  CAS  Google Scholar 

  27. Perk LR, Vosjan MJ, Visser GW, Budde M, Jurek P, Kiefer GE, et al. p-Isothiocyanatobenzyl-desferrioxamine: a new bifunctional chelate for facile radiolabeling of monoclonal antibodies with zirconium-89 for immuno-PET imaging. Eur J Nucl Med Mol Imaging. 2010;37:250–9.

    Article  PubMed  CAS  Google Scholar 

  28. Wang H, Cai W, Chen K, Li ZB, Kashefi A, He L, et al. A new PET tracer specific for vascular endothelial growth factor receptor 2. Eur J Nucl Med Mol Imaging. 2007;34:2001–10.

    Article  PubMed  CAS  Google Scholar 

  29. Holland JP, Sheh Y, Lewis JS. Standardized methods for the production of high specific-activity zirconium-89. Nucl Med Biol. 2009;36:729–39.

    Article  PubMed  CAS  Google Scholar 

  30. Takahashi N, Haba A, Matsuno F, Seon BK. Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide. Cancer Res. 2001;61:7846–54.

    PubMed  CAS  Google Scholar 

  31. Cai W, Wu Y, Chen K, Cao Q, Tice DA, Chen X. n vitro and in vivo characterization of 64Cu-labeled Abegrin, a humanized monoclonal antibody against integrin alpha v beta 3. Cancer Res. 2006;66:9673–81.

    Article  PubMed  CAS  Google Scholar 

  32. Cai W, Chen K, Mohamedali KA, Cao Q, Gambhir SS, Rosenblum MG, et al. PET of vascular endothelial growth factor receptor expression. J Nucl Med. 2006;47:2048–56.

    PubMed  CAS  Google Scholar 

  33. Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS. 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. J Nucl Med. 2010;51:1293–300.

    Article  PubMed  CAS  Google Scholar 

  34. Borjesson PK, Jauw YW, Boellaard R, de Bree R, Comans EF, Roos JC, et al. Performance of immuno-positron emission tomography with zirconium-89-labeled chimeric monoclonal antibody U36 in the detection of lymph node metastases in head and neck cancer patients. Clin Cancer Res. 2006;12:2133–40.

    Article  PubMed  Google Scholar 

  35. Tsujie M, Uneda S, Tsai H, Seon BK. Effective anti-angiogenic therapy of established tumors in mice by naked anti-human endoglin (CD105) antibody: differences in growth rate and therapeutic response between tumors growing at different sites. Int J Oncol. 2006;29:1087–94.

    PubMed  CAS  Google Scholar 

  36. Matsuno F, Haruta Y, Kondo M, Tsai H, Barcos M, Seon BK. Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies. Clin Cancer Res. 1999;5:371–82.

    PubMed  CAS  Google Scholar 

  37. Cai W, Ebrahimnejad A, Chen K, Cao Q, Li ZB, Tice DA, et al. Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice. Eur J Nucl Med Mol Imaging. 2007;34:2024–36.

    Article  PubMed  CAS  Google Scholar 

  38. Cai W, Chen K, He L, Cao Q, Koong A, Chen X. Quantitative PET of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody. Eur J Nucl Med Mol Imaging. 2007;34:850–8.

    Article  PubMed  CAS  Google Scholar 

  39. Heskamp S, van Laarhoven HW, Molkenboer-Kuenen JD, Franssen GM, Versleijen-Jonkers YM, Oyen WJ, et al. ImmunoSPECT and immunoPET of IGF-1R expression with the radiolabeled antibody R1507 in a triple-negative breast cancer model. J Nucl Med. 2010;51:1565–72.

    Article  PubMed  Google Scholar 

  40. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25.

    Article  PubMed  CAS  Google Scholar 

  41. Jefferis R, Lefranc MP. Human immunoglobulin allotypes: possible implications for immunogenicity. MAbs. 2009;1:332–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the University of Wisconsin Carbone Cancer Center, the NIH through the UW Radiological Sciences Training Program 5 T32 CA009206-32, NCRR 1UL1RR025011, a DOD BCRP Postdoctoral Fellowship, and a DOD PCRP IDEA Award. The authors also thank Dr. Jason P. Holland and Dr. Jason S. Lewis for sharing their expertise on 89Zr production and radiochemistry, Dr. Anna Wu and Dr. David M. Goldenberg for helpful discussions, Dr. Martin Shafer at the University of Wisconsin State Hygiene Laboratory for performing the ICPMS study, and Dr. Jamey P. Weichert and Mohammed Farhoud for their help with the PET scans.

Conflicts of interest

B.R.L. is an employee of TRACON Pharmaceuticals, Inc. The other authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Radiology, University of Wisconsin - Madison, Madison, WI, USA

    Hao Hong, Yunan Yang & Weibo Cai

  2. Department of Medical Physics, University of Wisconsin - Madison, Madison, WI, USA

    Gregory W. Severin, Jonathan W. Engle, Yin Zhang, Todd E. Barnhart, Robert J. Nickles & Weibo Cai

  3. Department of Medicine, University of Wisconsin - Madison, Madison, WI, USA

    Glenn Liu

  4. University of Wisconsin Carbone Cancer Center, Room 7137, 1111 Highland Ave, Madison, WI, 53705-2275, USA

    Glenn Liu & Weibo Cai

  5. TRACON Pharmaceuticals, Inc, San Diego, CA, USA

    Bryan R. Leigh

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  1. Hao Hong
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Correspondence to Weibo Cai.

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Hong, H., Severin, G.W., Yang, Y. et al. Positron emission tomography imaging of CD105 expression with 89Zr-Df-TRC105. Eur J Nucl Med Mol Imaging 39, 138–148 (2012). https://doi.org/10.1007/s00259-011-1930-x

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  • DOI: https://doi.org/10.1007/s00259-011-1930-x

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