Abstract
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.