Targeted alpha-particle therapy (TAT) might be a relevant therapeutic strategy to circumvent resistance to conventional therapies in the case of HER2-positive metastatic cancer. Single-domain antibody fragments (sdAb) are promising vehicles for TAT because of their excellent in vivo properties, high target affinity, and fast clearance kinetics. This study combines the cytotoxic α-particle emitter bismuth-213 (²¹³Bi) and HER2-targeting sdAbs. The in vitro specificity, affinity, and cytotoxic potency of the radiolabeled complex were analyzed on HER2^pos cells. Its in vivo biodistribution through serial dissections and via Cherenkov and micro-single-photon emission computed tomography (CT)/CT imaging was evaluated. Finally, the therapeutic efficacy and potential associated toxicity of [²¹³Bi]Bi-DTPA-2Rs15d were evaluated in a HER2^pos tumor model that manifests peritoneal metastasis. In vitro, [²¹³Bi]Bi-DTPA-2Rs15d bound HER2^pos cells in a HER2-specific way. In mice, high tumor uptake was reached already 15 min after injection, and extremely low uptake values were observed in normal tissues. Co-infusion of gelofusine resulted in a 2-fold reduction in kidney uptake. Administration of [²¹³Bi]Bi-DTPA-2Rs15d alone and in combination with trastuzumab resulted in a significant increase in median survival. We describe for the very first time the successful labeling of an HER2-sdAb with the α-emitter ²¹³Bi, and after intravenous administration, revealing high in vivo stability and specific accumulation in target tissue and resulting in an increased median survival of these mice especially in combination with trastuzumab. These results indicate the potential of [²¹³Bi]Bi-DTPA-sdAb as a new radioconjugate for TAT, alone and as an add-on to trastuzumab for the treatment of HER2^pos metastatic cancer.

中文翻译：

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213Bi标记的sdAb在卵巢癌临床前模型中的治疗效果。

在HER2阳性转移癌的情况下，靶向α粒子疗法（TAT）可能是规避对常规疗法耐药的一种相关治疗策略。单域抗体片段（sdAb）由于其出色的体内特性，高靶标亲和力和快速清除动力学而成为有希望的TAT载体。这项研究结合了具有细胞毒性的α粒子发射体铋213（²¹³ Bi）和靶向HER2的sdAb。在体外的特异性，亲和力，和细胞毒性放射性标记的络合物的效力上HER2进行分析^POS细胞。通过连续解剖和通过其体内生物分布对Cherenkov和微单光子发射计算机断层扫描（CT）/ CT成像进行了评估。最后，在表现出腹膜转移的HER2 ^pos肿瘤模型中评估了[ ²¹³ Bi] Bi-DTPA-2Rs15d的治疗效果和潜在的相关毒性。在体外，[ ²¹³ Bi] Bi-DTPA-2Rs15d以HER2特异性方式结合HER2 ^pos细胞。在小鼠中，注射后15分钟已经达到了很高的肿瘤吸收率，并且在正常组织中观察到极低的吸收值。共输注明珠丝氨酸可导致肾脏摄取减少2倍。[ ^213的管理单独使用Bi] Bi-DTPA-2Rs15d并与曲妥珠单抗联合使用可显着增加中位生存期。我们首次描述了用α-发射体²¹³ Bi成功标记HER2-sdAb ，并在静脉内给药后揭示了高体内稳定性和靶组织中的特异性蓄积，并导致这些小鼠的中位生存期增加，特别是与曲妥珠单抗联合使用。这些结果表明，[ ²¹³ Bi] Bi-DTPA-sdAb单独用作TAT的新型放射性结合物，也可能作为曲妥珠单抗的附加物治疗HER2 ^pos转移性癌症。