Abstract

Purpose

Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS. The current study aims to advance this system for alpha-particle therapy of OS.

Methods

The hu3F8 antibody was radiolabeled with actinium-225, and the safety and therapeutic efficacy of the [²²⁵Ac]Ac-DOTA-hu3F8 were evaluated in both orthotopic murine xenografts of OS and spontaneously occurring OS in canines.

Results

Significant antitumor activity was proven in both cases, leading to improved overall survival. In the murine xenograft’s case, tumor growth was delayed by 16–18 days compared to the untreated cohort as demonstrated by bioluminescence imaging. The results were further validated with magnetic resonance imaging at 33 days after treatment, and microcomputed tomography and planar microradiography post-mortem. Histological evaluations revealed radiation-induced renal toxicity, manifested as epithelial cell karyomegaly and suggestive polyploidy in the kidneys, suggesting rapid recovery of renal function after radiation damage. Treatment of the two canine patients delayed the progression of metastatic spread, with an overall survival time of 211 and 437 days and survival beyond documented metastasis of 111 and 84 days, respectively.

Conclusion

This study highlights the potential of hu3F8-based alpha-particle therapy as a promising treatment strategy for OS.

中文翻译：

---

α粒子发射体标记的抗 GD2 人源化抗体对骨肉瘤的治疗效果——概念验证研究

摘要

目的

目前骨肉瘤（OS）的治疗预后较差，特别是对于转移和复发的患者，这凸显了迫切需要新的靶向治疗来提高生存率。靶向α粒子疗法通过识别肿瘤相关抗原的放射性标记分子选择性地将细胞毒性有效负载递送至肿瘤。我们最近展示了 FDA 批准的人源化抗 GD2 抗体 hu3F8 作为 OS 放射性药物成像靶向递送载体的潜力。目前的研究旨在推进该系统用于 OS 的 α 粒子治疗。

方法

hu3F8抗体采用actinium-225放射性标记，[²²⁵Ac]Ac-DOTA-hu3F8的安全性和治疗效果在 OS 的原位鼠异种移植物和犬科动物自发发生的 OS 中进行了评估。

结果

两种情况均证明具有显着的抗肿瘤活性，从而提高了总体生存率。生物发光成像显示，在小鼠异种移植物中，与未治疗组相比，肿瘤生长延迟了 16-18 天。治疗后 33 天的磁共振成像以及尸检后的显微计算机断层扫描和平面显微放射线摄影进一步验证了结果。组织学评估显示辐射引起的肾毒性，表现为肾脏上皮细胞核肿大和提示性多倍体，表明辐射损伤后肾功能迅速恢复。两名犬患者的治疗延缓了转移扩散的进展，总生存时间分别为 211 天和 437 天，记录转移后的生存时间分别为 111 天和 84 天。

结论

这项研究强调了基于 hu3F8 的 α 粒子疗法作为一种有前景的 OS 治疗策略的潜力。