Skip to main content
SpringerLink
Log in

Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab

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

Abstract

This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5·106 Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 µg unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%±4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%±2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with 149Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach.

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 a
Fig. 5

Similar content being viewed by others

References

  1. Hall EJ. Radiobiology for the radiologist. 4th edn. Philadelphia: Lippincott, 1994.

  2. Maecklis RM, Lin JY, Beresford B, Achter RW, Hines JJ, Humm JL. Cellular kinetics, dosimetry, and radiobiology of alpha-particle radioimmunotherapy: inducing of apoptosis. Radiat Res 1992; 130:220–226.

    PubMed  Google Scholar 

  3. McDevitt MR, Ma D, Simon J, Frank RK, Scheinberg D. Design of225Ac-radiopharmaceuticals. Appl Rad Isot 2002; 57:841–847.

    Article  CAS  Google Scholar 

  4. Allen BJ, Blagojevic N. Alpha and beta emitting radiolanthanides in targeted cancer therapy: the potential role for terbium-149. Nucl Med Commun 1996; 17:40–47.

    CAS  PubMed  Google Scholar 

  5. Zalutsky MR, Vaidyanathan G. Astatine-211 labeled radiotherapeuticals: an emerging approach to targeted alpha particle therapy. Current Pharm Design 2000; 6:1433–1455.

    CAS  Google Scholar 

  6. Huber R, Seidl C, Schmid E, Seidenschwang S, Becker K-F, Schuhmacher C, Apostolidis C, Nikula T, Kremmer E, Schwaiger M, Senekowitsch-Schmidtke. Locoregional alpha-radioimmunotherapy of intraperitoneal tumor cell dissemination using a tumor-specific monoclonal antibody. Clin Cancer Res 2003; 9:3922–3928.

    Google Scholar 

  7. Jurcic JG, Larson SM, Sgouros G, McDevitt MR, Finn RD, Divgi CR, Ballangrud ÅM, Hamacher KA, Ma D, Humm JL, Brechbiel MW, Molinet R, Scheinberg DA. Targeted α-particle immunotherapy for myeloid leukemia. Blood 2002; 100:1233–1239.

    CAS  PubMed  Google Scholar 

  8. McDevitt MR, Sgouros G, Finn RD, Humm JL, Jurcic JG, Larson SM, Scheinberg DA. Radioimmunotherapy with alpha-emitting radionuclides. Eur J Nucl Med 1998; 25:1341–1351.

    CAS  PubMed  Google Scholar 

  9. Allen BJ, Goozee G, Imam S, Sarkar S, Leigh J, Beyer G-J. Targeted cancer therapy: The potential role of terbium-149. 6th International Conference on Radiopharmaceutical Dosimetry, Gatlington, Tenn. (USA), May 7–10, 1996, CERN-PPE/96–127, 1996

  10. Charlton DE, Utteridge TD, Allen BJ. Theoretical treatment of human hemopoietic stem cell survival following irradiation by alpha particles. Int J Radiat Biol 1998; 74:111–118.

    Article  CAS  PubMed  Google Scholar 

  11. Allen BJ. Can alpha immunotherapy succeed where other modalities have failed? Nucl Med Commun 1999; 20:205–207.

    CAS  PubMed  Google Scholar 

  12. Wagner HN Jr, Wiseman GA, Marcus CS, et al. Administration guidelines for radioimmunotherapy of Non-Hodgkin’s lymphoma with90Y-labeled anti-CD20 monoclonal antibody. J Nucl Med 2002; 43:267–272.

    CAS  PubMed  Google Scholar 

  13. Miederer M, Seidl C, Beyer G-J, Charlton DE, Vranješ-Đurić SD, Čomor JJ, Huber R, Nikula T, Apostolidis C, Schuhmacher C, Becker K-F, Senekowitsch-Schmidtke R. Comparison of the radiotoxicity of two alpha emitting immunoconjugates, terbium-149 and bismuth-213, directed against a tumor-specific, exon 9 deleted (d9) E-cadherin adhesion protein. Radiat Res 2002; 159:612–620.

    Google Scholar 

  14. Vranješ SD, Miederer M, Čomor JJ, Soloviev D, Beyer G-J and the ISOLDE collaboration. Labeling of monoclonal antibodies with 149-Tb for targeted alpha therapy. J Lab Comp Radiopharm 2001; 44:718–720.

    Google Scholar 

  15. Ghetie MA, Richardson J, Tucker T, Jones D, Uhr JW, Vitetta ES. Disseminated or localized growth of a human B-cell tumor (Daudi) in SCID mice. Int J Cancer 1990; 45:481–485.

    CAS  PubMed  Google Scholar 

  16. McDevitt MR, Ma D, Lai LT, Simon J, Borchardt P, Frank RK, Wu K, Pellegrini V, Curcio MJ, Miederer M, Bander NH, Scheinberg DA. Tumor therapy with targeted atomic nanogenerators. Science 2001; 294:1537–1540.

    Article  CAS  PubMed  Google Scholar 

  17. Firestone RB. Table of isotopes, 8th edn. New York: Wiley-Interscience, 1996.

  18. Kugler E. The ISOLDE facility. Hyperfine Interactions 2000; 129:23–42.

    Article  CAS  Google Scholar 

  19. Beyer G-J, Čomor JJ, Daković M, Soloviev D, Tamburella C, Hagebø E, Allan B, Dmitriev SN, Zaitseva NG, Starodub GY, Molokanova LG, Vranješ SD, Miederer M, and the ISOLDE Collaboration. Production routes of the alpha emitting 149-Tb for medical application. Radiochim Acta 2002; 90:247–252.

    CAS  Google Scholar 

  20. Beyer G-J, Offord RE, Künzi G, Jones RML, Ravn U, Aleksandrova Y, Werlen RC, Mäcke H, Lindroos M, Jahn S, Tengblad O, and the ISOLDE Collaboration. Biokinetics of monoclonal antibodies labeled with radio-lanthanides and 225-Ac in xenografted nude mice. J Label Compd Radiopharm 1995; 37:229–530.

    Google Scholar 

  21. Beyer G-J, Münze R, Fromm WD, Franke WG, Henke E, Khalkin VA, Lebedev NA. Spallation produced 167-Tm for medical application. In: Medical radionuclide imaging 1980, vol 1. Vienna: IAEA; 1981:587 (IAEA-SM-247/60).

  22. Beyer G-J, Offord R, Künzi G, Aleksandrova Y, Ravn U, Jahn S, Backe J, Tengblad O, Lindroos M, and the ISOLDE Collaboration. The influence of EDTMP-concentration on the biodistribution of radio-lanthanides and225Ac in tumor bearing mice. Nucl Med Biol 1997; 24:367–372.

    Article  CAS  PubMed  Google Scholar 

  23. Beyer G-J, Bergmann R, Schomäcker K, Rösch F, Schäfer G, Kulikov EV, Novgorodov AF. Comparison of the biodistribution of225Ac and radiolanthanides as citrate complexes. Isotopenpraxis 1990; 26:111–114.

    CAS  Google Scholar 

  24. Beyer G-J, Herrmann E, Khalkin VA. Chemical effects related to different radioactive decay processes of cerium isotopes chelated with different polyaminocarbonic acids. Dubna: JINR P 12–7758, 1974.

  25. Beyer G-J, Herrmann E. Chemical effects of nuclear transformations in lanthanide chelate complexes. In: Proceedings of the COST Chemistry Action D18, Mid Term Evaluation Workshop on Lanthanide Chemistry for Diagnosis and Therapy, Heidelberg (Germany), July 22–25, 2002, p 26.

  26. Stabin MG. MIRDOSE: personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 1996; 37:538–546.

    CAS  PubMed  Google Scholar 

  27. Breeman WAP, DeJong M, Krenning EP. Labeling of DOTA-peptides at high specific activities. ICFE’5, Geneva, Switzerland, August 24–29, 2003, CO4-SL8, abstract book p 197.

  28. Beyer G-J, Ruth TJ. The role of electromagnetic separators in the production of radiotracers for bio-medical research and nuclear medical applications. NIM B 2003; 204:694–700.

    Article  CAS  Google Scholar 

Download references

Acknowledgement

The authors wish to thank Prof. S. Larson (MSKCC New York) for his very valuable discussion during the preparation of this manuscript and Prof. D. Scheinberg (MSKCC New York) for providing the rituximab-DTPA bioconjugate used in this study. The support by the Swiss National Science Foundation Project Nr. 31–53672.98 and by the European Commission within the HPRI-Program Nr. HPRI-CT-1999–00018 is acknowledged.

Author information

Authors and Affiliations

  1. Division of Nuclear Medicine, University Hospital of Geneva, 24 Rue Micheli du Crest, 1211, Geneva 14, Switzerland

    G.-J. Beyer, D. Soloviev & F. Buchegger

  2. Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, USA

    M. Miederer

  3. Laboratory of Radioisotopes, Vinča Institute of Nuclear Sciences, Belgrade, Serbia and Montenegro

    S. Vranješ-Đurić

  4. Laboratory of Physics, Vinča Institute of Nuclear Sciences, Belgrade, Serbia and Montenegro

    J. J. Čomor

  5. Department of Medical Biochemistry, University Medical Center, Geneva, Switzerland

    G. Künzi & O. Hartley

  6. Clinic of Nuclear Medicine, Technical University of Munich, Munich, Germany

    R. Senekowitsch-Schmidtke

Authors
  1. G.-J. Beyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Miederer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Vranješ-Đurić
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. J. Čomor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Künzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O. Hartley
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Senekowitsch-Schmidtke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. Soloviev
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F. Buchegger
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

and the ISOLDE Collaboration

Corresponding author

Correspondence to G.-J. Beyer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beyer, GJ., Miederer, M., Vranješ-Đurić, S. et al. Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab. Eur J Nucl Med Mol Imaging 31, 547–554 (2004). https://doi.org/10.1007/s00259-003-1413-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-003-1413-9

Keywords

Search

Navigation