Pharmacokinetic variability of 225Ac and 213Bi from vector labeled 225Ac cancer therapy as a function of vector type (antibody vs. small molecule)

Objectives Actinium-225 (T1/2 = 9.9 days) labeled targeted radiopharmaceuticals’ pharmacokinetics are determined by the choice of targeting vector used (i.e. antibody, small molecule, etc.). The decay of 225Ac results in the release of the decay daughters from the targeting vector. For example, decay of 225Ac-labeled agent in the blood results with the longest lived daughter 213Bi (T1/2 = 46 minutes) accumulating in the cortex region of the kidneys and is associated with the majority of the radiation dose to the kidneys. Depending on the targeting vector accumulation within different normal tissues the dominant supplier of unbound 213Bi to the kidneys may be altered. In this study we used two different targeting vectors (antibody and a small molecule peptidomimetic) labeled with 225Ac against breast cancer (BC) and castrate resistant prostate cancer (CRPC), respectively, to determine the pharmacokinetics of unbound 213Bi to the kidneys. Methods To compare pharmacokinetics differences between targeting vectors, we selected the 7.16.4 antibody, which is targeted to Erbb2, and a PSMA-targeted small molecule peptidomimetic. The 7.16.4 antibody was labeling with 225Ac and the resulting agent, 225Ac-7.16.4, was injected into neu-N mice bearing Erbb2+ tumors. The 225Ac-labeled PSMA-targeted peptidomimetic was injected into mice bearing PSMA+ tumors. For both models at select time points the mice were sacrificed, organs removed, and measured for activity. Select organs were measured directly after harvesting, and continuously measured over a period of several hours to determine the amount of unbound 213Bi compared to the intact 225Ac-labeled targeting vector present in the selected organ. Differentiation in the detection of these two isotopes is delicate as only the 213Bi emits photons captured in the gamma well counter; therefore fits to the time activity data from the gamma well counter using the half-lives of the two isotopes can distinguish between the intact 225Ac-labeled agent and unbound 213Bi. Results The use of the small molecule vector for the CRPC murine model showed uptake of unbound 213Bi in the kidneys at all time points and the main supplying organ of unbound 213Bi was the liver. In the BC murine model using an antibody the blood was the main supplier of unbound 213Bi to the kidneys. These results were combined with the different micro-scale distribution in the kidneys for 213Bi and the respective vector-225Ac to determine the radiation dose to kidneys and other normal organs. Conclusions This study demonstrated that the use of different targeting vectors for delivery of 225Ac alters the pharmacokinetics and suppliers of unbound 213Bi, to the kidneys. These properties are important for translation to clinical studies as in vivo imaging cannot distinguish between the intact 225Ac-labeled agent and the unbound 213Bi, resulting in an overestimation of the average radiation dose to kidneys and an underestimation of the average radiation dose to the supplying organ (blood and liver, respectively).

JOSEFSSON Anders;  NEDROW Jessie;  RAY Sangeeta;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  POMPER Martin;  SGOUROS G.;  HOBBS Robert F.; 

2018-07-17

SOC NUCLEAR MEDICINE INC

JRC110545

0161-5505,   

http://jnm.snmjournals.org/content/59/supplement_1/137.abstract?sid=59a45f0f-d5e1-4eb8-af90-cea...,    https://publications.jrc.ec.europa.eu/repository/handle/JRC110545,