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

Objectives To evaluate possible late side effects of ²²⁷Th-rituximab, the long-term radiotoxicity was investigated.

Methods BALB/c mice were injected with saline, cold rituximab or 50, 200 or 1000 kBq/kg ²²⁷Th-rituximab and followed for up to one year. In addition, nude mice with Raji xenografts treated with 50, 200, 400, 600 or 1000 kBq/kg 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 1000 kBq/kg dosage resulted in decreased body-weight. There was a significant but temporary decrease in WBC and platelet count in mice treated with 1000 and 400 kBq/kg ²²⁷Th-rituximab. Therefore, the no-observed-adverse-effect-level (NOAEL) was 200 kBq/kg. The maximum tolerated activity was between 600 and 1000 kBq/kg. No significant signs of toxicity were observed in histological sections in any examined tissue. The maximum tolerated dose to bone marrow was estimated to be 3.6 Gy.

Conclusions Therapeutic 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-tumor activity data in a CD20 positive xenograft mouse model, indicate that therapeutic effects could be obtained with relatively safe dosage levels of the radioimmunoconjugate.

Research Support The study was supported by the Norwegian Research Council and the Norwegian Cancer Society as well as Algeta ASA.