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Preclinical Development of [211At]meta- astatobenzylguanidine ([211At]MABG) as an Alpha Particle Radiopharmaceutical Therapy for Neuroblastoma
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2022-07-21 , DOI: 10.1158/1078-0432.ccr-22-0400
Vandana Batra 1, 2 , Minu Samanta 1 , Mehran Makvandi 3 , David Groff 1 , Paul Martorano 3 , Jimmy Elias 1 , Pietro Ranieri 1 , Matthew Tsang 1 , Catherine Hou 3 , Yimei Li 2, 4 , Bruce Pawel 5 , Daniel Martinez 6 , Ganesan Vaidyanathan 7 , Sean Carlin 3 , Daniel A Pryma 2, 3 , John M Maris 1, 2
Affiliation  

Purpose: [131I]meta-iodobenzylguanidine ([131I]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However, relapses in the bone marrow are common. [211At]meta-astatobenzylguanidine ([211At] MABG) is an alpha particle emitter with higher biological effectiveness and short path length which effectively sterilizes microscopic residual disease. Here we investigated the safety and antitumor activity [211At]MABG in preclinical models of neuroblastoma. Experimental Design: We defined the maximum tolerated dose (MTD), biodistribution, and toxicity of [211At]MABG in immunodeficient mice in comparison with [131I]MIBG. We compared the antitumor efficacy of [211At]MABG with [131I]MIBG in three murine xenograft models. Finally, we explored the efficacy of [211At]MABG after tail vein xenografting designed to model disseminated neuroblastoma. Results: The MTD of [211At]MABG was 66.7 MBq/kg (1.8 mCi/kg) in CB17SC scid−/− mice and 51.8 MBq/kg (1.4 mCi/kg) in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Biodistribution of [211At]MABG was similar to [131I]MIBG. Long-term toxicity studies on mice administered with doses up to 41.5 MBq/kg (1.12 mCi/kg) showed the radiotherapeutic to be well tolerated. Both 66.7 MBq/kg (1.8 mCi/kg) single dose and fractionated dosing 16.6 MBq/kg/fraction (0.45 mCi/kg) × 4 over 11 days induced marked tumor regression in two of the three models studied. Survival was significantly prolonged for mice treated with 12.9 MBq/kg/fraction (0.35 mCi/kg) × 4 doses over 11 days [211At]MABG in the disseminated disease (IMR-05NET/GFP/LUC) model (P = 0.003) suggesting eradication of microscopic disease. Conclusions: [211At]MABG has significant survival advantage in disseminated models of neuroblastoma. An alpha particle emitting radiopharmaceutical may be effective against microscopic disseminated disease, warranting clinical development.

中文翻译:

[211At]偏苯甲基胍 ([211At]MABG) 作为阿尔法粒子放射性药物治疗神经母细胞瘤的临床前开发

目的:[131I]间碘苄基胍 ([131I]MIBG) 是一种全身性靶向放射治疗药物,用于在神经母细胞瘤中传递 β 粒子辐射。然而,骨髓复发很常见。[211At]间位苄基胍([211At]MABG)是一种α粒子发射体,具有较高的生物有效性和较短的路径长度,可有效灭菌微小残留疾病。在这里,我们研究了 [211At]MABG 在神经母细胞瘤临床前模型中的安全性和抗肿瘤活性。实验设计:我们与[131I]MIBG 相比,确定了免疫缺陷小鼠中[211At]MABG 的最大耐受剂量(MTD)、生物分布和毒性。我们在三种小鼠异种移植模型中比较了 [211At]MABG 与 [131I]MIBG 的抗肿瘤功效。最后,我们探讨了尾静脉异种移植后 [211At]MABG 的功效,旨在模拟播散性神经母细胞瘤。结果:CB17SC scid−/− 小鼠中 [211At]MABG 的 MTD 为 66.7 MBq/kg (1.8 mCi/kg),NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) 中的 MTD 为 51.8 MBq/kg (1.4 mCi/kg)老鼠。[211At]MABG 的生物分布与[131I]MIBG 相似。对小鼠给予高达 41.5 MBq/kg (1.12 mCi/kg) 剂量的长期毒性研究表明,放射治疗具有良好的耐受性。在所研究的三个模型中的两个模型中,66.7 MBq/kg (1.8 mCi/kg) 单剂量和分次给药 16.6 MBq/kg/分数 (0.45 mCi/kg) × 4 在 11 天内均诱导了显着的肿瘤消退。在播散性疾病 (IMR-05NET/GFP/LUC) 模型中,在 11 天内接受 12.9 MBq/kg/分数 (0.35 mCi/kg) × 4 剂 [211At]MABG 治疗的小鼠的存活时间显着延长(P = 0. 003)建议根除微观疾病。结论:[211At]MABG 在播散性神经母细胞瘤模型中具有显着的生存优势。发射α粒子的放射性药物可能对微小播散性疾病有效,值得临床开发。
更新日期:2022-07-21
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