Department of Molecular Imaging and Theranostics, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan.
OncoTherapy Science Inc., Kanagawa, Japan.
Cancer Sci. 2022 Feb;113(2):721-732. doi: 10.1111/cas.15235. Epub 2021 Dec 21.
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 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 Ac. Competitive inhibition and cell binding assays showed that specific binding of Ac-labeled OTSA101 to SYO-1 synovial sarcoma cells was comparable to that of the imaging agent 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 Ac-labeled OTSA101 for tumors was 7.8 Bd higher than that of Y-labeled OTSA101. Y- and Ac-labeled OTSA101 decreased tumor volume and prolonged survival. Ac-labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. Ac-labeled OTSA101 induced a larger amount of necrosis and apoptosis than 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. 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 Ac-labeled OTSA101 is a promising therapeutic option for synovial sarcoma.
滑膜肉瘤是一种罕见的青少年和青年人群中发生的肿瘤。晚期疾病的预后较差，总生存率为 12-18 个月。卷曲同源物 10（FZD10）在大多数滑膜肉瘤中过度表达，使其成为有前途的治疗靶点。β-放射免疫疗法（RIT）与 Y 标记的抗-FZD10 抗体 OTSA101 的 1 期试验结果表明需要提高疗效。本研究评估了用 α-发射器 Ac 标记的 OTSA101 的 α-RIT 的潜力。竞争抑制和细胞结合试验表明， Ac 标记的 OTSA101 与 SYO-1 滑膜肉瘤细胞的特异性结合与成像剂 In 标记的 OTSA101 相当。生物分布研究表明，SYO-1 肿瘤的摄取量高，除血液外，正常器官的摄取量低。剂量学研究表明， Ac 标记的 OTSA101 对肿瘤的生物有效剂量（BED）比 Y 标记的 OTSA101 高 7.8 Bd。 Y 和 Ac 标记的 OTSA101 均能减小肿瘤体积并延长生存时间。 Ac 标记的 OTSA101 使 60%的小鼠达到完全缓解，且未观察到复发。 Ac 标记的 OTSA101 诱导的坏死和凋亡比 Y 标记的 OTSA101 更多，尽管细胞增殖减少相当。正常器官和组织的 BED 是可以耐受的；除了暂时的体重减轻外，没有观察到与治疗相关的死亡或明显的毒性。 Ac 标记的 OTSA101 为肿瘤提供了较高的 BED，并使滑膜肉瘤小鼠模型 SYO-1 达到 60%的完全缓解。 Ac 标记的 OTSA101 进行 RIT 是治疗滑膜肉瘤的一种很有前途的选择。
