An Integrated Analysis of Four Targeted Thorium Conjugates to Assess the 227 Th and 223 Ra Distribution and Tissue-Related Radiation

Abstract

Introduction:

α-emitting radiopharmaceuticals are increasingly being evaluated as potential cancer therapeutics. In this study, the authors evaluated the distribution of thorium-227 (²²⁷Th) and its first daughter nuclide, radium-223 (²²³Ra), by analyzing tissue activity data from monkey studies from different antibody-based targeted thorium conjugates (hereafter called “conjugates”). This study clarified the extent of elimination by physical decay and redistribution from tissues for both radionuclides.

Methods:

In monkey biodistribution studies for four different conjugates, animals were sacrificed at multiple time points, and organ activities of ²²⁷Th and ²²³Ra were measured by direct γ counting. These values were compared to the maximally expected organ activities based on physical decay as the sole elimination path to evaluate the impact of redistribution from tissues. Whole-body activities in cancer patients, measured with high-purity germanium detectors during a first-in-human study of a CD22-targeting conjugate, were evaluated similarly to determine whether they aligned with the overall patterns seen in tissue data.

Results:

The integrated analysis demonstrated that for all conjugates, the physical decay appeared to be the main elimination path for ²²⁷Th without a strong redistribution from organs, whereas ²²³Ra shows a fast and strong redistribution (≥90%) from most of the tissues except for bone (∼0%) and (large) intestine. The lack of redistribution from bone as well as the high radioactivity in the intestine is consistent with data obtained with ²²³Ra chloride in monkeys and humans. These findings were independent of the assessed compound, target, dose, and administered activity. The observation in monkeys that physical decay is the main elimination path for ²²⁷Th and that ²²³Ra undergoes a fast additional elimination in a typical tissue was consistent with clinical whole-body radioactivity data.

Conclusions:

The overarching consistency of the findings regarding tissue redistribution of ²²⁷Th and ²²³Ra across different conjugates and the consistency with clinical observations of whole body radioactivity in patients emphasize the importance of considering the potential redistribution of long-lived daughter nuclides of radionuclides used in therapeutic applications in humans.