Immunoglobulins as Radiopharmaceutical Vectors

  • Danielle J. VugtsEmail author
  • Guus A. M. S. van Dongen


With the introduction of the magic bullet concept by Ehrlich and the subsequent development of hybridoma technology by Kohler and Milstein, the world of target-specific protein-based drugs was opened. Since then, numerous immunoglobulins and a few dozen radioimmunoconjugates have been approved by the US Food and Drug Administration (US FDA) and the European Medicines Agency (EMA). In this chapter, we will discuss the array of natural and engineered immunoglobulins that are available as vectors for imaging and therapy as well as their in vivo modes of action. Several critical aspects of the accessibility and expression of targets related to the use of radioimmunoconjugates for imaging and therapy will be also discussed. These two introductory sections are followed by the core of the chapter in which we address the selection of appropriate radionuclide-immunoglobulin combinations, the possible applications of immunoPET and immunoSPECT, and how radiolabeled immunoglobulins can be evaluated.


Monoclonal antibodies PET SPECT Immunoglobulins Imaging Therapy Radioimmunodetection Radioimmunotherapy Biologicals 


  1. 1.
    Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8(6):473–80.PubMedCrossRefGoogle Scholar
  2. 2.
    Brekke OH, Sandlie I. Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov. 2003;2(1):52–62.PubMedCrossRefGoogle Scholar
  3. 3.
    Delves PJ, Martin SJ, Burton DR, Roitt IM. Roitt’s essential immunology. 13th ed. Chichester/Hoboken: John Wiley & Sons; 2017.Google Scholar
  4. 4.
    Vazquez-Lombardi R, Phan TG, Zimmermann C, Lowe D, Jermutu L, Christi D. Challenges and opportunities for non-antibody scaffold drugs. Drug Discov Today. 2015;20(10):1271–83.PubMedCrossRefGoogle Scholar
  5. 5.
    Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20(7):838–47.PubMedCrossRefGoogle Scholar
  6. 6.
    Liu LM. Antibody glycosylation and its impact on the pharmacokinetics and pharmacodynamics of monoclonal antibodies and Fc-fusion proteins. J Pharm Sci. 2015;104(6):1866–84.PubMedCrossRefGoogle Scholar
  7. 7.
    Weiner GJ. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer. 2015;15(6):361–70.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Reichert JM. Antibodies to watch in 2017. MAbs. 2017;9(2):167–81.PubMedCrossRefGoogle Scholar
  9. 9.
    Sehlin D, Fang XTT, Cato L, Antoni G, Lannfelt L, Syvanen S. Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease. Nat Commun. 2016;7:10759.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    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(5):586–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Goldenberg DM. Targeted therapy of cancer with radiolabeled antibodies. J Nucl Med. 2002;43(5):693–713.PubMedGoogle Scholar
  12. 12.
    Jain RK. Transport of molecules, particles and cells in solid tumors. Annu Rev Biomed Eng. 1999;1:241–63.PubMedCrossRefGoogle Scholar
  13. 13.
    Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev. 2007;26(3–4):489–502.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Wagner M, Wiig H. Tumor interstitial fluid formation, characterization, and clinical implications. Front Oncol. 2015;5:115.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Olafsen T, Wu AM. Novel antibody vectors for imaging. Semin Nucl Med. 2010;40(3):167–81.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lamberts LE, Williams SP, Terwisscha van Scheltinga AG, Lub-de Hooge MN, Schroder CP, Gietema JA, et al. Antibody positron emission tomography imaging in anticancer drug development. J Clin Oncol. 2015;33(13):1491–504.PubMedCrossRefGoogle Scholar
  17. 17.
    Jauw YW, Menke-van der Houven van Oordt CW, Hoekstra OS, Hendrikse NH, Vugts DJ, Zijlstra JM, et al. Immuno-positron emission tomography with zirconium-89 labeled monoclonal antibodies in oncology: what can we learn from initial clinical trials? Front Pharmacol. 2016;7:131.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32(1):40–51.PubMedCrossRefGoogle Scholar
  19. 19.
    Visser GW, Klok RP, Klein-Gebbink JW, Ter Linde T, Van Dongen GA, Molthoff CF. Optimal quality Iodine-131-monoclonal antibodies upon high dose labeling in a large reaction volume and temporarily coating the antibody with iodogen. J Nucl Med. 2001;42(3):509–19.PubMedGoogle Scholar
  20. 20.
    Lindmo T, Boven E, Cuttitta F, Fedorko J, Bunn PA Jr. Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Methods. 1984;72(1):77–89.PubMedCrossRefGoogle Scholar
  21. 21.
    Van Gog FB, Rakenhoff RH, Snow GB, van Dongen GA. Rapid elimination of mouse/human chimeric monoclonal antibodies in nude mice. Cancer Immunol Immunother. 1997;44(2):103–11.PubMedCrossRefGoogle Scholar
  22. 22.
    Fleuren ED, Versleijen-Jonkers YM, Heskamp S, van Herpen CM, Oyen WJ, van der Graaf WT, Boerman OC. Theranostic applications of antibodies in oncology. Mol Oncol. 2014;8(4):799–812.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Nayak TK, Brechbiel MW. Radioimmuno imaging with longer-lived positron-emitting radionuclides: potentials and challenges. Bioconjug Chem. 2009;20(5):825–41.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Van Dongen GA, Poot AJ, Vugts DJ. PET imaging with radiolabeled antibodies and tyrosine kinase inhibitors: immuno-PET and TKI-PET. Tumor Biol. 2012;33(3):607–15.CrossRefGoogle Scholar
  25. 25.
    Bourgeois M, Bailly C, Frindel M, Guerard F, Cherel M, Faivre-Chauvet A, et al. Radioimmunoconjugates for treating cancer: recent advances and current opportunities. Expert Opin Biol Ther. 2017;17(7):813–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Moek KL, Giesen D, Kok IC, de Groot DJA, Jalving M, Fehrmann RS, et al. Theranostics using antibodies and antibody-related therapeutics. J Nucl Med. 2017;58(Suppl 2):83S–90S.PubMedCrossRefGoogle Scholar
  27. 27.
    Knowles SM, Wu AM. Advances in immuno-positron emission tomography: antibodies for molecular imaging in oncology. J Clin Oncol. 2012;30(31):3884–92.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Gaykema SB, Schröder CP, Vitfell-Rasmussen J, Chua S, Oude Munnink TH, Brouwers AH, et al. 89Zr-trastuzumab and 89Zr-bevacizumab PET to evaluate the effect of the HSP90 inhibitor NVP-AUY922 in metastatic breast cancer patients. Clin Cancer Res. 2014;20(15):3945–54.PubMedCrossRefGoogle Scholar
  29. 29.
    Arjaans M, Oude Munnink TH, Oosting SF, Terwisscha van Scheltinga AF, Gietema JA, Garbacik ET, et al. Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. Cancer Res. 2013;73(11):3347–55.PubMedCrossRefGoogle Scholar
  30. 30.
    Van der Veldt AA, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN, et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling anti-angiogenic drugs. Cancer Cell. 2012;21(1):82–91.PubMedCrossRefGoogle Scholar
  31. 31.
    Van Asselt SJ, Oosting SF, Brouwers AH, Bongaerts AH, de Jong JR, Lub-de Hooge MN, et al. Everolimus reduces 89Zr-bevacizumab tumor uptake in patients with neuroendocrine tumors. J Nucl Med. 2014;55(7):1087–92.PubMedCrossRefGoogle Scholar
  32. 32.
    Gebhart G, Lamberts LE, Wimana Z, Garcia C, Emonts P, Ameye L, et al. Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial. Ann Oncol. 2017;27(4):619–24.CrossRefGoogle Scholar
  33. 33.
    Jauw YW, Huisman MC, Nayak TK, Vugts DJ, Christen R, Naegelen VM, et al. Assessment of target-mediated uptake with immuno-PET: analysis of a phase I clinical trial with an anti-CD44 antibody. EJNMMI Res. 2018;8(1):6.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Freise A, Wu AM. In vivo imaging with antibodies and engineered fragments. Mol Immunol. 2015;67(2 Pt A):142–52.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Wu A. Engineered antibodies for molecular imaging of cancer. Methods. 2014;65(1):139–47.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Danielle J. Vugts
    • 1
    Email author
  • Guus A. M. S. van Dongen
    • 1
  1. 1.Department of Radiology & Nuclear MedicineVU University Medical CenterAmsterdamThe Netherlands

Personalised recommendations