Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody

Abstract

Clinical therapeutic studies using 225 Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of 225 Ac. The purpose of this study was to determine the amount of 225 Ac and non-equilibrium progeny in the mouse kidney after the injection of 225 Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with 225 Ac-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 213 Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess 213 Bi 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 213 Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from nonequilibrium excess 213 Bi (0.31 (SD 0.11) Gy kBq −1 ) represented ~46% of the total. For the medulla the dose contribution from excess 213 Bi (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 225 Ac-huM195 with non-equilibrium excess 213 Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of 225 Ac radioimmunotherapy.

Therapeutic efficacy and toxicity of 225Ac-labelled vs. 213Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis

“…Following intravenous injection of 225 Ac-huM195 immunoconjugates (22.2 kBq) into tumour-free mice the absorbed dose estimates were 15 Gy to the renal cortex and 23 Gy to the renal medulla. Almost 80% (18.2 Gy) of the estimated absorbed dose to the renal medulla was delivered by free 213 Bi generated by extrarenal decay of 225 Ac [23]. Therefore, the overall success of 225 Ac radioimmunotherapy is largely dependent on methods to reduce renal accumulation of the α-particle-emitting daughter nuclides 221 Fr and 213 Bi.…”

“…Such short-lived radionuclides might affect the efficacy of targeted therapy, particularly after systemic administration, because the time could be too short to allow saturation of tumour targets before the majority of the activity has decayed [23]. To optimize therapeutic efficacy it has been suggested that α-emitters with substantially longer half-lives be used such as 225 Ac (t 1/2 10 days) [24].…”

“…On the other hand, stable coupling of 225 Ac together with its α-particleemitting daughter nuclides 221 Fr, 217 At, and 213 Bi to antibodies or peptides is not possible with the chelating compounds currently available. The decay of 225 Ac to 221 Fr releases a recoil kinetic energy significantly greater than the chemical bond energies of any chelating agent, resulting in loss of the daughter nuclide from the chelate molecule [23]. Therefore, if 225 Ac does not decay within a tumour cell, the daughter radionuclides might spread in the circulation causing toxic side effects.…”

α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies—Part 1

“…4A) (50). The average absorbed dose to the kidneys was determined to be 0.77 GyÁkBq 21 , of which 60% was attributed to nonequilibrium 213 Bi excess (50).…”

“…Schwartz et al evaluated the contribution of nonequilibrium 213 Bi to kidney dose in mice via g-ray spectroscopy immediately after tissue harvest and at secular equilibrium ( Fig. 4A) (50). The average absorbed dose to the kidneys was determined to be 0.77 GyÁkBq 21 , of which 60% was attributed to nonequilibrium 213 Bi excess (50).…”