Published in:
01-01-2010 | Original Article
Assessment of long-term radiotoxicity after treatment with the low-dose-rate alpha-particle-emitting radioimmunoconjugate 227Th-rituximab
Authors:
Jostein Dahle, Thora J. Jonasdottir, Helen Heyerdahl, Jahn M. Nesland, Jørgen Borrebæk, Anne Kristine Hjelmerud, Roy H. Larsen
Published in:
European Journal of Nuclear Medicine and Molecular Imaging
|
Issue 1/2010
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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.