Abstract 4344: Broader therapeutic window via combining sodium ascorbate for protecting radioactive antibodies from radiolysis and sodium perchlorate for blocking sodium iodide symporter in radioimmunotherapy with astatine-211
Authors: Hiroki Takashima, Shino Manabe, Ryo Tsumura, Yoshikatsu Koga, Takahiro Anzai, Hiromitsu Haba, Anri Inaki, Masahiro Yasunaga
Journal: Cancer Research (2025)

Background: Increasing attention has been paid to developing new cancer treatments with alpha particles characterized by a high linear energy transfer (LET) and a range of 50-100 µm in tissue, which is equivalent to 5-10 cells. Due to the short path length, tumor-selective accumulation of alpha particles is pivotal for achieving a reasonable therapeutic window. Previously, we demonstrated that reactive oxygen species (ROS) generated via the radiolysis of water in storage solution denature antibodies labeled with astatine-211, an alpha emitter, which results in disrupted specific binding activity of astatinated antibodies. On the other hand, free radical scavengers such as sodium ascorbate (SA) can quench ROS and protect radioactive antibodies from astatine-211-induced denaturation. The antibody denaturation significantly attenuates tumor accumulation and the antitumor activity of antibodies labeled with astatine-211, whereas SA protection successfully maintains them. On the other hand, stabilization with SA has no impact on distribution to normal organs, including the uptake in the stomach and thyroid caused by free astatine-211 released from antibodies. Thus, in this study, to reduce the accumulation in these organs, we combined sodium perchlorate (SP), a sodium iodide symporter (NIS) inhibitor, with SA protection and evaluated antitoxic activity. Although it is well known that NIS blockade can reduce halogen radionuclide accumulation in these organs, the antitoxic effect and tolerability in radioimmunotherapy (RIT) with astatine-211 under SA protection remain unclear. Methods: Mice bearing tumor were pretreated with PBS or 1.2 µmol/g SP and intravenously administered 1 MBq of antibody labeled with astatine-211. We evaluated the impact of the NIS blockade on biodistribution. The accumulation in the thyroid was visualized by single-photon emission computed tomography/computed tomography (SPECT/CT). Toxicity after RIT was evaluated by body weight change and blood tests. Results: Pretreatment with SP significantly reduced the percentage of injected dose per gram of tissue (%ID/g) for stomach and stomach contents without decreasing tumor accumulation (stomach, P = 0.020; stomach contents, P = 0.013). SPECT/CT images showed that the pretreatment resulted in lower signals in the thyroid and stomach contents. NIS blockade contributed to significantly more rapid recovery from body weight loss after the injection of astatine-211-labeled antibody (P = 0.002). Findings in blood tests were comparable between these groups, showing the tolerability of the combination. Conclusion: Combining SA protection against radiolysis and NIS blockade with SP is tolerable in RIT with astatine-211, leading to a broader therapeutic window. Citation Format: Hiroki Takashima, Shino Manabe, Ryo Tsumura, Yoshikatsu Koga, Takahiro Anzai, Hiromitsu Haba, Anri Inaki, Masahiro Yasunaga. Broader therapeutic window via combining sodium ascorbate for protecting radioactive antibodies from radiolysis and sodium perchlorate for blocking sodium iodide symporter in radioimmunotherapy with astatine-211 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4344.