Radiation Dosimetry of Actinium (Ac-225) Rosopatamab Tetraxetan (Ac-RT): Anti-PSMA antibody labeled with an alpha emitter for targeted therapy of metastatic castration resistant prostate cancer (mCRPC).

Introduction: Rosopatamab Tetraxetan (also known as DOTA-huJ591 mAb) was labeled with Ac-225, an alpha emitter for targeted radionuclide therapy (TRT) of mCRPC. Radiation dosimetry of Ac-RT was estimated based on PET and SPECT imaging studies with three different chemical surrogates for Ac-RT such as ⁸⁹Zr-DFO-RT (Zr-RT), ¹¹¹In-DOTA-RT (In-RT), or ¹⁷⁷Lu-DOTA-RT (In-RT). Relative biological effectiveness (RBE) for alpha emitting radionuclides is generally assumed to be higher (RBE = 3-7) compared to that with radionuclides emitting high energy beta particles (RBE = 1). Radiation dosimetry of Ac-RT with different RBE values is compared based on biodistribution studies with ⁸⁹Zr, ¹¹¹In, and ¹⁷⁷Lu labeled RT. .

Methods: Biodistribution data for In-RT and Lu-RT, was based on planar whole body imaging studies (J Nucl Med 46:634, 2005). The % injected activity (IA) in different organs for each radiotracer was used to obtain the time‐activity‐curve (TAC) and time integrated activity coefficient (TIAC), also known as residence time. Ac‐225 TIACs for all source organs were obtained by using mono‐ or bi‐exponential fits to the TACs (%IA vs. time data with the physical decay of Ac-225 added). Then the equation obtained from the exponential fit was used to analytically integrate the data over time using 3D‐RD‐S, a software package developed by Rapiddosimetry that implements the MIRD S‐value formalism. Previously, Ac-RT dosimetry was estimated using Zr-RT PET imaging studies (J Nucl Med 41:2093, 2014). Based on the three radiotracers, Ac-225 dosimetry was compared at RBE of 5. To deliver 2 Gy to bone marrow, the amount of Ac-RT that can be injected was estimated. Also, based on In-RT, Ac-RT dosimetry was estimated for RBE values of 1-5.

Results: Ac-RT dosimetry estimated based on three different radiotracers is compared in Table 1. While the dose to marrow is similar with the 3 tracers, the dose to liver and kidney are significantly different. To deliver 2 Gy to bone marrow, the amount of Ac-RT that can be injected is 6.06 MBq based on Zr-RT compared to 5.5 with In-RT, and only 4.4 GBq with Lu-RT. Dose to critical organs increases with increasing values of RBE used (Table 2) in the dosimetry model.

Table 1: Comparison of Ac-RT dosimetry based on three radiotracers

Table 2. Ac-RT dosimetry at different RBE values

Conclusions: The results clearly suggest that the radiation dosimetry of Ac-RT depends on the chemical surrogate, the imaging method, and the value of RBE used in the dosimetry model. Since RBE may depend on the radiation sensitivity of a critical organ, choosing an RBE value of 5 for all alpha emitters and for all critical organs may not be appropriate. Clinical safety and toxicology data are essential to determine the maximum tolerated dose (MTD) for Ac-RT.

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