Abstract
Clinical therapeutic studies using 225Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of 225Ac. The purpose of this study was to determine the amount of 225Ac and non-equilibrium progeny in the mouse kidney after the injection of 225Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with 225Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess 213Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess 213Bi reaching the kidney (γ-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq−1, of which 0.46 (SD 0.16) Gy kBq−1 (i.e. 60%) was due to non-equilibrium excess 213Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess 213Bi (0.31 (SD 0.11) Gy kBq−1) represented ∼46% of the total. For the medulla the dose contribution from excess 213Bi (0.81 (SD 0.28) Gy kBq−1) was ∼80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq−1 following administration of 225Ac-huM195 with non-equilibrium excess 213Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of 225Ac radioimmunotherapy.
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