Development of separation technology for the removal of radium-223 from targeted thorium conjugate formulations. Part I: purification of decayed thorium-227 on cation exchange columns

Abstract

Targeted thorium conjugates (TTCs) are being explored as a potential future platform for specific tumor targeting pharmaceuticals. In TTCs, the alpha emitting radionuclide thorium-227 (227Th) with a half-life of 18.697 d is labeled to targeting moieties, such as monoclonal antibodies (mAbs). The amount of daughter nuclide radium-223 (223Ra, t1/2 = 11.435 d) will increase during manufacture and distribution, and so a technology for purification is required to assure an acceptable level of 223Ra is administrated to the patient. Since 223Ra is the only progeny of 227Th with a long half-life (days), the progenies of 223Ra will have a very limited stay in the formulation once 223Ra is removed. The focus in this study has, therefore, been on the removal of 223Ra. In this study, the sorption and separation of 223Ra (radium(II)) and 227Th (thorium(IV)) on cation exchange columns has been evaluated as a purification method of decayed 227Th (i.e. prior to radiolabelling of a mAb and formation of TTC). The goal is to minimize the sorption of 227Th and maximize the sorption of 223Ra. Statistical experimental design with formulation and process parameters, including buffered formulations comprising citrate and acetate, at various concentrations and pH, presence of free radical scavenger and chelator, and resin amount have been evaluated for impact on the purification process. The studies have been interpreted by the aid of multivariate data analysis. The correlations between design of experimental variables and sorption are summarized by regression models. The predictive accuracy of radionuclide sorption was given by standard deviation and 95% confidence intervals originating from statistical cross validation. Experimental results and statistical models for citrate-buffered formulations verified reproducible and acceptable sorption levels of 223Ra and 227Th under selected conditions. For acetate-buffered formulations, prediction of 227Th sorption was influenced by complex variable relationships and hence a risk of obtaining irreproducibility. Fine-tuned variable levels showed, however, variable combinations predicting high sorption of 223Ra (>90%) and low sorption of 227Th (<3%) also for the acetate-buffered formulations. The optimal separation conditions should be decided based on tuning the variables levels for 223Ra in the citrate-buffered formulations, while for acetate, the optimal separation should be based on tuning variable levels for 227Th sorption. The ionic strength of the formulation also seemed to affect the radionuclide sorption. Labeling of an antibody-chelator conjugate with purified 227Th (i.e. preparation of TTC) was successful in the selected citrate-buffered formulations tested.