Tumor Anti-Vascular Alpha Therapy with a ²¹²Pb in vivo alpha generator: A mathematical model to improve treatment planning

Aim: Tumor anti-vascular alpha therapy (TAVAT) is an attractive approach for the treatment of solid tumors by targeting tumor vasculature. Direct targeting of endothelial cells (ECs) of tumor vasculature by alpha emitters disrupts tumor capillaries and thus inhibits tumor growth. The high LET and short range of alpha particles are effective in irradiating ECs while limiting toxicity to the surrounding tissue. TAVAT overcomes the limitation of poor penetration of radiolabeled antibodies; therefore, it allows rapid localization of the injected activity. The aim of this study was to build a mathematical model to describe the pharmacokinetics and the absorbed doses of ²¹²Pb-labeled monoclonal antibodies (mabs) targeting antigens/receptors expressed in tumor vasculature.

Methods: A compartmental model for tumor vasculature (10% of tumor volume), plasma (2.92 l), the distribution volume of the remainder of the human body (8.75 l) and the dose-limiting organ, i. e. kidneys (0.33 l) was developed and implemented in the software SAAMII (v2.3, University of Washington, WA). The model was constructed based on physiological, chemical and physical properties with parameter values from the literature. For a fixed dose of 10 Gy in tumor vasculature, the absorbed doses of radiolabeled mabs and free radionuclides in tumor vasculature, kidneys and plasma were calculated for various fitted amounts (0.15-15.2 pmol) for different molar activities (0.1-10.9 MBq/pmol). The contributions to the absorbed doses in the investigated spaces were calculated for both alpha and beta emissions of each radionuclide. The absorbed doses in plasma and kidneys vasculature for different antigen densities (5-500 nmol/l) were calculated. The excretion of free ²¹²Bi after being released from the chelator due to a preceding disintegration was studied by including a physiological kidney model¹.

Results: The simulations show that the prescribed dose in tumor vasculature of 10 Gy was achieved in the case of 5 nmol/l of antigen density by injecting 1.6 MBq of ²¹²Pb-labeled mabs with a molar activity of 10.9 MBq/pmol, the absorbed dose both in kidneys vasculature and plasma was 0.03 Gy. The relative contributions of the emitted radiation to the absorbed doses are shown in the table.

Conclusions: The presented mathematical model of ²¹²Pb-labeled mabs allows the simulation of the pharmacokinetics of radiolabeled and unlabeled mabs and released radionuclides in the human body. It holds promise to predict and investigate optimal dosing regimens (activity and amounts) for different prescribed doses to tumor vasculature using different radiopharmaceuticals. Dosimetry calculations allow evaluating the therapeutic efficacy and safety of TAVAT. 1) Kletting et al. Modeling and Predicting Tumor Response in Radioligand Therapy. J Nucl Med. 2019;60(1):65-70.