Predicting tumour and organ dose in α-radiopharmaceutical therapy: a <sup>89</sup>Zr-based dosimetric approach for <sup>225</sup>Ac.

Abstract

The aim of this study was to assess whether zirconium-89 (89Zr)-labelled antibodies can act as a surrogate for actinium-225 (225Ac)-labelled antibodies to predict tumour- and organ dose. To this end, we performed ex vivo biodistribution and dosimetry studies with two anti-CAIX antibodies (hG250 and FcRn(-)hG250), radiolabelled with 89Zr and 225Ac, in a renal cell carcinoma mouse model.MethodsBALB/c nude mice bearing subcutaneous SK-RC-52 tumours were injected intravenously with 25-50 kBq 225Ac-labelled or 1 MBq 89Zr-labelled anti-CAIX antibody, at equal protein dose. Organ and tumour absorbed doses were calculated based on the uptake data at 4, 24, 72, and 168 h for FcRn(-)hG250 and 24, 72, and 168 h for hG250. The predictive value of 89Zr for 225Ac was evaluated in both groups, by comparing the predicted 225Ac absorbed dose (based on 89Zr-antibody) and the measured 225Ac absorbed dose.ResultsThe biodistribution profile of the theranostic pair 89Zr/225Ac was comparable for FcRn(-)hG250. For hG250, significant discrepancies between tumour, spleen and liver uptake were observed. The predicted 225Ac tumour dose was overestimated by 3.9 ± 2.0 Gy (6 ± 50.6%) and underestimated by 1413.7 ± 629.1 Gy (69 ± 44.5%) in the FcRn(-)hG250 and hG250 groups, respectively. The deviation of the predicted versus measured 225Ac-dose in off-target organs was most notable in liver and spleen for both antibodies.ConclusionThis study highlights variability in the predictive accuracy of the 89Zr/225Ac theranostic pair for tumour and organ dosimetry in a ccRCC mouse model, depending on the antibody used. FcRn(-)hG250 enabled accurate tumour dose estimation, whereas hG250 showed mismatched uptake limiting prediction, possibly due to inherent differences in the properties and biological effects of both 225Ac and 89Zr. These findings underscore the need to further investigate how 89Zr-PET can be used for 225Ac-TRT dose prediction.