Early Normal Tissue Effects and Bone Marrow Relative Biological Effectiveness for an Actinium 225-Labeled HER2/neu-Targeting Antibody

Abstract

In this study we have determined the dose-independent relative biological effectiveness (RBE2) of bone marrow for an anti-HER2/neu antibody labeled with the alpha-particle emitter actinium-225 (225Ac). Hematologic toxicity is often a consequence of radiopharmaceutical therapy (RPT) administration, and dosimetric guidance to the bone marrow is required to limit toxicity. Female neu/N transgenic mice (MMTV-neu) were intravenously injected with 0-16.65 kBq of the alpha-particle emitter labeled antibody, 225Ac-DOTA-7.16.4 and sacrificed at 1-9 days after-treatment. Complete blood counts (CBC) were performed. Femurs and tibias were collected, and bone marrow was isolated from one femur and tibia, and counted for radioactivity. Contralateral intact femurs were fixed, decalcified and assessed by histology. Marrow cellularity was the biological endpoint selected for RBE2 determination. For the reference radiation, both femurs of the mice were photon irradiated with 0-5 Gy, using a small animal radiation research platform. Response as measured by cellularity for the alpha-particle emitter RPT and the external beam radiotherapy were linear and linear quadratic, respectively, as a function of absorbed dose. The resulting dose-independent RBE2 for bone marrow was 6. As alpha-emitter RPT gains prominence, preclinical studies evaluating RBE, in vivo, will be important in relating to human experience with beta-particle emitter RPT. Such normal tissue RBE evaluations will help mitigate unexpected toxicity in αRPT.