Clinical Application of Targeted Alpha Therapy Using Astatine

Targeted alpha therapy is gaining prominence owing to its superior therapeutic efficacy compared with conventional radionuclide therapies using beta emitters. Astatine (211At, half-life: 7.2 h) has recently emerged as a promising alpha emitter, along with actinium (225Ac) and lead (212Pb). It can be produced domestically by irradiating natural bismuth targets with alpha particles using a 30 MeV cyclotron. Chemically analogous to iodine, astatine accumulates in differentiated thyroid cancer cells via the sodium/iodide symporter and demonstrated significant antitumor effects in a xenograft model. At The University of Osaka, we completed the first-in-human investigator-initiated clinical trial using [211At]sodium astatide (NaAt) in patients with metastatic thyroid cancer refractory to radioiodine (131I) therapy. The disappearance of iodine-avid lesions and a marked reduction in serum thyroglobulin levels (a tumor marker) were observed, suggesting clinical efficacy. In addition, we developed 211At-labeled compounds targeting the prostate-specific membrane antigen (PSMA), and a clinical trial is currently underway to confirm their efficacy and safety in preclinical studies. Furthermore, pan-tumor-targeting probes, including amino acid derivatives specific for L-type amino acid transporter 1 (LAT1) and antibodies targeting ephrin type-A receptor 2 (EphA2), are under active development and optimization for clinical applications. Targeted alpha therapy using astatine has great potential to significantly alter the future landscape of cancer therapy.