Because of their rapid tumor accumulation and normal tissue clearance, single-domain antibody fragments (sdAbs) are an attractive vehicle for developing radiotherapeutics labeled with the α-emitter ²¹¹At. Herein, we have evaluated iso-[²¹¹At]AGMB-PODS, a prosthetic agent that combines a functionality for residualizing radiohalogens with a phenyloxadiazolyl methylsulfone (PODS) moiety for site-specific sdAb conjugation. Iso-[²¹¹At]AGMB-PODS and its radioiodinated analogue were evaluated for thiol-selective conjugation to anti-HER2 5F7 sdAb bearing a C-terminus GGC tail. Both radiohalogenated PODS-5F7GGC conjugates were synthesized in good radiochemical yields and retained high binding affinity on HER2-positive BT474 breast carcinoma cells. Iso-[²¹¹At]AGMB-PODS-5F7GGC was considerably more stable in vitro than its maleimide analogue in the presence of cysteine and human serum albumin (HSA) and exhibited excellent tumor uptake and high in vivo stability. Superior tumor-to-kidney activity ratios were seen for both radiohalogenated PODS-5F7GGC conjugates compared with [¹⁷⁷Lu]Lu-DOTA-PODS-5F7GGC. These results suggest that iso-[²¹¹At]AGMB-PODS-5F7GGC warrants further evaluation for the treatment of HER2-expressing malignancies.

中文翻译：

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使用新型残留修复剂对 HER2 靶向单域抗体片段进行位点特异性放射性卤化

由于其快速的肿瘤积累和正常的组织清除，单域抗体片段 (sdAb) 是开发用 α 发射体 211 At 标记的放射治疗剂的有吸引力的^载体。在此，我们评估了iso -[ ²¹¹ At]AGMB-PODS，这是一种修复剂，它结合了残留放射性卤素的功能和用于位点特异性 sdAb 缀合的苯恶二唑基甲基砜 (PODS) 部分。异-[ ²¹¹At]AGMB-PODS 及其放射性碘化类似物被评估用于与带有 C 末端 GGC 尾巴的抗 HER2 5F7 sdAb 的硫醇选择性缀合。两种放射性卤化的 PODS-5F7GGC 偶联物都以良好的放射化学产率合成，并且对 HER2 阳性 BT474 乳腺癌细胞保持高结合亲和力。在半胱氨酸和人血清白蛋白 (HSA) 存在的情况下，异-[ ^{211 At]AGMB-PODS-5F7GGC}在体外比其马来酰亚胺类似物稳定得多，并且表现出出色的肿瘤摄取和高体内稳定性。与 [ ¹⁷⁷ Lu] Lu-DOTA-PODS-5F7GGC 相比，两种放射性卤化 PODS-5F7GGC 偶联物均具有更高的肿瘤-肾脏活性比。这些结果表明iso -[ ²¹¹ At]AGMB-PODS-5F7GGC 保证对 HER2 表达恶性肿瘤的治疗进行进一步评估。