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Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12‐18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of β‐radioimmunotherapy (RIT) with the  90 Y‐labeled anti‐FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α‐RIT with OTSA101 labeled with the α‐emitter  225 Ac. Competitive inhibition and cell binding assays showed that specific binding of  225 Ac‐labeled OTSA101 to SYO‐1 synovial sarcoma cells was comparable to that of the imaging agent  111 In‐labeled OTSA101. Biodistribution studies showed high uptake in SYO‐1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of  225 Ac‐labeled OTSA101 for tumors was 7.8 Bd higher than that of  90 Y‐labeled OTSA101.  90 Y‐ and  225 Ac‐labeled OTSA101 decreased tumor volume and prolonged survival.  225 Ac‐labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed.  225 Ac‐labeled OTSA101 induced a larger amount of necrosis and apoptosis than  90 Y‐labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment‐related mortality or obvious toxicity, except for temporary body weight loss, was observed.  225 Ac‐labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO‐1. RIT with  225 Ac‐labeled OTSA101 is a promising therapeutic option for synovial sarcoma.

FZD10‐targeted α‐radioimmunotherapy with 225 Ac‐labeled OTSA101 achieves complete remission in a synovial sarcoma model