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Assessment of long-term radiotoxicity after treatment with the low-dose-rate alpha-particle-emitting radioimmunoconjugate 227Th-rituximab

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

Abstract

Purpose

The anti-CD20 antibody rituximab labelled with the α-particle-emitting radionuclide 227Th is of interest as a radiotherapeutic agent for treatment of lymphoma. Complete regression of human lymphoma Raji xenografts in 60% of mice treated with 200 kBq/kg 227Th-rituximab has been observed. To evaluate possible late side effects of 227Th-rituximab, the long-term radiotoxicity of this potential radiopharmaceutical was investigated.

Methods

BALB/c mice were injected with saline, cold rituximab or 50, 200 or 1,000 kBq/kg 227Th-rituximab and followed for up to 1 year. In addition, nude mice with Raji xenografts treated with various doses of 227Th-rituximab were also included in the study. Toxicity was evaluated by measurements of mouse body weight, white blood cell (WBC) and platelet counts, serum clinical chemistry parameters and histological examination of tissues.

Results

Only the 1,000 kBq/kg dosage resulted in decreased body weight of the BALB/c mice. There was a significant but temporary decrease in WBC and platelet count in mice treated with 400 and 1,000 kBq/kg 227Th-rituximab. Therefore, the no-observed-adverse-effect level (NOAEL) was 200 kBq/kg. The maximum tolerated activity was between 600 and 1,000 kBq/kg. No significant signs of toxicity were observed in histological sections in any examined tissue. There were significantly (p < 0.05), but transiently, higher concentrations of serum bile acids and aspartate aminotransferase in mice treated with either 227Th-rituximab or non-labelled antibody when compared with control mice. The maximum tolerated dose to bone marrow was between 2.1 and 3.5 Gy.

Conclusion

Therapeutically relevant dose levels of 227Th-rituximab were well tolerated in mice. Bone marrow suppression, as indicated by decrease in WBC count, was the dose-limiting radiotoxicity. These toxicity data together with anti-tumour activity data in a CD20-positive xenograft mouse model indicate that therapeutic effects could be obtained with relatively safe dosage levels of the radioimmunoconjugate.

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Acknowledgements

This work was supported by the Norwegian Cancer Society, the Norwegian Research Council and Helse Sør-Øst. We are grateful to the Histology Laboratory at Division for Pathology, The Norwegian Radium Hospital for making and staining the histological sections of mouse organs. We also appreciate the services provided by the Animal Department at the Norwegian Radium Hospital. We also thank Dr. Olav Kaalhus, The Norwegian Radium Hospital, for help with the statistical analysis of the clinical chemistry data. Algeta ASA has a patent pending for using 227Th for radioimmunotherapy and has provided research support for this study. Jørgen Borrebæk is an employee of Algeta ASA. Roy H. Larsen, Thora J. Jonasdottir and Jostein Dahle own stocks in Algeta ASA.

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Authors and Affiliations

  1. Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, 0310, Oslo, Norway

    Jostein Dahle, Helen Heyerdahl, Anne Kristine Hjelmerud & Roy H. Larsen

  2. Small Animal Section, Department of Companion Animal Clinical Sciences, Norwegian School of Veterinary Science, 0033, Oslo, Norway

    Thora J. Jonasdottir

  3. Division of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, 0310, Oslo, Norway

    Jahn M. Nesland

  4. Faculty Division The Norwegian Radium Hospital, Medical Faculty, University of Oslo, 0310, Oslo, Norway

    Jahn M. Nesland

  5. Algeta AS, 0411, Oslo, Norway

    Jørgen Borrebæk

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  1. Jostein Dahle
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  2. Thora J. Jonasdottir
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  3. Helen Heyerdahl
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  4. Jahn M. Nesland
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  6. Anne Kristine Hjelmerud
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  7. Roy H. Larsen
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Correspondence to Jostein Dahle.

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Dahle, J., Jonasdottir, T.J., Heyerdahl, H. et al. Assessment of long-term radiotoxicity after treatment with the low-dose-rate alpha-particle-emitting radioimmunoconjugate 227Th-rituximab. Eur J Nucl Med Mol Imaging 37, 93–102 (2010). https://doi.org/10.1007/s00259-009-1197-7

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