Dosimetry and preclinical evaluation of longterm radiotoxicity following treatment with 212Pb alpha-radioimmunotherapy targeting CD20

Abstract

Background Radioimmunotherapy (RIT) with α-emitters represents an attractive alternative for the treatment of refractory Non-Hodgkin lymphoma (NHL) due to the high linear energy transfer and short path length of α-radiation in tissues. We have previously shown that α-RIT with [212Pb]Pb-TCMC-rituximab is potentially useful for treatment of NHL. In this study, we performed radiation dosimetry and evaluated the long-term toxicity in mice to determine safety of [212Pb]Pb-TCMC-rituximab,.

Results Biodistribution data obtained after intravenous administration of [212Pb]Pb-TCMC-rituximab (185 kBq) in healthy mice were used to calculate the absorbed radiation doses from [212Pb]Pb-TCMC-rituximab. Analyses show that the alveolar-interstitial, kidneys, and spleen receive the highest dose.

In order to evaluate the toxicity of RIT for up to 9 months, [212Pb]Pb-TCMC-rituximab was administered intravenously in healthy C57BL/6 mice (277.5 and 555 kBq) and in a B-NHL immunocompetent mouse model (277.5 kBq, specific activity of 37 or 370 MBq/mg). Our previous study revealed a high efficacy of [212Pb]Pb-TCMCrituximab at 277.5 kBq and that activities of 185–370 kBq of [212Pb]Pb-TCMC-rituximab were well-tolerated. However, in this long-term study, toxicity emerged in healthy mice after four months. The median survival for the 277.5 and 555 kBq groups were 189 and 161 days, respectively. There was no significant hepatic toxicity, but there was a significant increase in urea and creatinine levels at 6 months, indicating long-term renal toxicity (p <0.001). These results were supported by histopathological data. Long-term renal toxicity is also observed in the toxicity study performed on tumor model with two specific activities of [212Pb]Pb-TCMC-rituximab. Nevertheless, this toxicity was reduced at 370 MBq/mg compared to 37 MBq/mg.

Conclusion This study shows that long-term toxicity is induced by [212Pb]Pb-TCMC-rituximab, particularly affecting the kidneys. However, it highlights that this renal toxicity can be reduced through optimization, possibly by modifying the specific activity of the treatment.