Skip to main content

Advertisement

SpringerLink
Log in

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Overexpression of CD146 in solid tumors has been linked to disease progression, invasion, and metastasis. We describe the generation of a 64Cu-labeled CD146-specific antibody and its use for quantitative immunoPET imaging of CD146 expression in six lung cancer models.

Methods

The anti-CD146 antibody (YY146) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with 64Cu. CD146 expression was evaluated in six human lung cancer cell lines (A549, NCI-H358, NCI-H522, HCC4006, H23, and NCI-H460) by flow cytometry and quantitative western blot studies. The biodistribution and tumor uptake of 64Cu-NOTA-YY146 was assessed by sequential PET imaging in athymic nude mice bearing subcutaneous lung cancer xenografts. The correlation between CD146 expression and tumor uptake of 64Cu-NOTA-YY146 was evaluated by graphical software while ex vivo biodistribution and immunohistochemistry studies were performed to validate the accuracy of PET data and spatial expression of CD146.

Results

Flow cytometry and western blot studies showed similar findings with H460 and H23 cells showing high levels of expression of CD146. Small differences in CD146 expression levels were found among A549, H4006, H522, and H358 cells. Tumor uptake of 64Cu-NOTA-YY146 was highest in CD146-expressing H460 and H23 tumors, peaking at 20.1 ± 2.86 and 11.6 ± 2.34 %ID/g at 48 h after injection (n = 4). Tumor uptake was lowest in the H522 model (4.1 ± 0.98 %ID/g at 48 h after injection; n = 4), while H4006, A549 and H358 exhibited similar uptake of 64Cu-NOTA-YY146. A positive correlation was found between tumor uptake of 64Cu-NOTA-YY146 (%ID/g) and relative CD146 expression (r 2 = 0.98, p < 0.01). Ex vivo biodistribution confirmed the accuracy of the PET data.

Conclusion

The strong correlation between tumor uptake of 64Cu-NOTA-YY146 and CD146 expression demonstrates the potential use of this radiotracer for imaging tumors that elicit varying levels of CD146. In the future, this tool may promote enhanced monitoring of therapeutic response and improved patient stratification.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.

    Article  PubMed  Google Scholar 

  2. Cosaert J, Quoix E. Platinum drugs in the treatment of non-small-cell lung cancer. Br J Cancer. 2002;87(8):825–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Miranda DM, Mamede M, Souza BR, et al. Molecular medicine: a path towards a personalized medicine. Rev Bras Psiquiatr. 2012;34(1):82–91.

    Article  PubMed  Google Scholar 

  4. Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med. 2010;363(4):301–4.

    Article  CAS  PubMed  Google Scholar 

  5. Knowles SM, Wu AM. Advances in immuno-positron emission tomography: antibodies for molecular imaging in oncology. J Clin Oncol. 2012;30(31):3884–92.

    Article  PubMed  PubMed Central  Google Scholar 

  6. van Dongen GA, Visser GW, Lub-de Hooge MN, de Vries EG, Perk LR. Immuno-PET: a navigator in monoclonal antibody development and applications. Oncologist. 2007;12(12):1379–89.

    Article  PubMed  Google Scholar 

  7. Fischer KR, Durrans A, Lee S, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527(7579):472–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene. 2005;24(50):7443–54.

    Article  CAS  PubMed  Google Scholar 

  9. Cho JY. Molecular diagnosis for personalized target therapy in gastric cancer. J Gastric Cancer. 2013;13(3):129–35.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zeng Q, Li W, Lu D, et al. CD146, an epithelial-mesenchymal transition inducer, is associated with triple-negative breast cancer. Proc Natl Acad Sci U S A. 2012;109(4):1127–32.

    Article  CAS  PubMed  Google Scholar 

  12. Wang Z, Yan X. CD146, a multi-functional molecule beyond adhesion. Cancer Lett. 2013;330(2):150–62.

    Article  CAS  PubMed  Google Scholar 

  13. Wang P, Qu Y, Li C, et al. Bio-functionalized dense-silica nanoparticles for MR/NIRF imaging of CD146 in gastric cancer. Int J Nanomedicine. 2015;10:749–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yang Y, Hernandez R, Rao J, et al. Targeting CD146 with a 64Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas. Proc Natl Acad Sci U S A. 2015;112(47):E6525–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Luo H, England CG, Graves SA, et al. PET imaging of VEGFR-2 expression in lung cancer with 64Cu-labeled ramucirumab. J Nucl Med. 2016;57(2):285–90.

    Article  PubMed  Google Scholar 

  16. Eaton SL, Hurtado ML, Oldknow KJ, et al. A guide to modern quantitative fluorescent western blotting with troubleshooting strategies. J Vis Exp. 2014;93, e52099.

    PubMed  Google Scholar 

  17. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58.

    Article  CAS  PubMed  Google Scholar 

  18. Uhlen M, Fagerberg L, Hallstrom BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.

    Article  PubMed  Google Scholar 

  19. American Cancer Society. Cancer facts & figures 2016. Atlanta: American Cancer Society; 2016.

    Google Scholar 

  20. Tripodis N, Demant P. Genetic analysis of three-dimensional shape of mouse lung tumors reveals eight lung tumor shape-determining (Ltsd) loci that are associated with tumor heterogeneity and symmetry. Cancer Res. 2003;63(1):125–31.

    CAS  PubMed  Google Scholar 

  21. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805(1):105–17.

    CAS  PubMed  Google Scholar 

  22. Esposito L, Conti D, Ailavajhala R, Khalil N, Giordano A. Lung cancer: are we up to the challenge? Curr Genomics. 2010;11(7):513–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Schmid-Bindert G, Zhou C. Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians. Ther Adv Med Oncol. 2012;4(1):19–29.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sahu A, Prabhash K, Noronha V, Joshi A, Desai S. Crizotinib: a comprehensive review. South Asian J Cancer. 2013;2(2):91–7.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jarantow SW, Bushey BS, Pardinas JR, et al. Impact of cell-surface antigen expression on target engagement and function of an epidermal growth factor receptor × c-MET bispecific antibody. J Biol Chem. 2015;290(41):24689–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Perez HL, Cardarelli PM, Deshpande S, et al. Antibody-drug conjugates: current status and future directions. Drug Discov Today. 2014;19(7):869–81.

    Article  CAS  PubMed  Google Scholar 

  27. Kristiansen G, Yu Y, Schluns K, Sers C, Dietel M, Petersen I. Expression of the cell adhesion molecule CD146/MCAM in non-small cell lung cancer. Anal Cell Pathol. 2003;25(2):77–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Oka S, Uramoto H, Chikaishi Y, Tanaka F. The expression of CD146 predicts a poor overall survival in patients with adenocarcinoma of the lung. Anticancer Res. 2012;32(3):861–4.

    PubMed  Google Scholar 

  29. Nowak D, Skwarek-Maruszewska A, Zemanek-Zboch M, Malicka-Blaszkiewicz M. Beta-actin in human colon adenocarcinoma cell lines with different metastatic potential. Acta Biochim Pol. 2005;52(2):461–8.

    CAS  PubMed  Google Scholar 

  30. Sugiura G, Kuhn H, Sauter M, Haberkorn U, Mier W. Radiolabeling strategies for tumor-targeting proteinaceous drugs. Molecules. 2014;19(2):2135–65.

    Article  PubMed  Google Scholar 

  31. Vosjan MJ, Perk LR, Visser GW, 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(4):739–43.

    Article  CAS  PubMed  Google Scholar 

  32. Gooden CS. Radiolabeling of monoclonal antibodies. Methods Mol Med. 2000;40:341–50.

    CAS  PubMed  Google Scholar 

  33. Rogers BE, Anderson CJ, Connett JM, et al. Comparison of four bifunctional chelates for radiolabeling monoclonal antibodies with copper radioisotopes: biodistribution and metabolism. Bioconjug Chem. 1996;7(4):511–22.

    Article  CAS  PubMed  Google Scholar 

  34. 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(6):850–8.

    Article  CAS  PubMed  Google Scholar 

  35. Cai W, Wu Y, Chen K, Cao Q, Tice DA, Chen X. In vitro and in vivo characterization of 64Cu-labeled Abegrin, a humanized monoclonal antibody against integrin alpha v beta 3. Cancer Res. 2006;66(19):9673–81.

    Article  CAS  PubMed  Google Scholar 

  36. Petkova SB, Akilesh S, Sproule TJ, et al. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol. 2006;18(12):1759–69.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the University of Wisconsin - Madison, the National Institutes of Health (NIBIB/NCI 1R01CA169365, P30CA014520, T32CA009206, and T32GM008349), the National Science Foundation (DGE-1256259), and the American Cancer Society (125246-RSG-13-099-01-CCE).

Author information

Author notes

    Authors and Affiliations

    1. Department of Radiology, University of Wisconsin - Madison, 1111 Highland Ave., Madison, WI, 53705-2275, USA

      Haiyan Sun, Anyanee Kamkaew, Dawei Jiang, Yunan Yang & Weibo Cai

    2. Department of Medical Physics, University of Wisconsin - Madison, Madison, WI, 53705, USA

      Christopher G. England, Reinier Hernandez, Stephen A. Graves, Todd E. Barnhart & Weibo Cai

    3. Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, 53705, USA

      Rebecca L. Majewski & Weibo Cai

    4. University of Wisconsin Carbone Cancer Center, Madison, WI, 53705, USA

      Weibo Cai

    Authors
    1. Haiyan Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Christopher G. England
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Reinier Hernandez
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Stephen A. Graves
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Rebecca L. Majewski
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Anyanee Kamkaew
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Dawei Jiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Todd E. Barnhart
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Yunan Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Weibo Cai
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Yunan Yang or Weibo Cai.

    Ethics declarations

    Conflicts of interest

    None.

    Ethical approval

    All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

    Additional information

    Haiyan Sun and Christopher G. England contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    ESM 1

    (DOCX 7062 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Sun, H., England, C.G., Hernandez, R. et al. ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer. Eur J Nucl Med Mol Imaging 43, 2169–2179 (2016). https://doi.org/10.1007/s00259-016-3442-1

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00259-016-3442-1

    Keywords

    Search

    Navigation