Dekempeneer Yana, Caveliers Vicky, Ooms Maarten, Maertens Dominic, Gysemans Mireille, Lahoutte Tony, Xavier Catarina, Lecocq Quentin, Maes Ken, Covens Peter, Miller Brian W, Bruchertseifer Frank, Morgenstern Alfred, Cardinaels Thomas, D'Huyvetter Matthias
Institute for Nuclear Materials Science, Belgian Nuclear Research Center (SCK CEN), 2400 Mol, Belgium.
In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium.
Mol Pharm. 2020 Sep 8;17(9):3553-3566. doi: 10.1021/acs.molpharmaceut.0c00580. Epub 2020 Aug 13.
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 properties, high target affinity, and fast clearance kinetics. This study combines the cytotoxic α-particle emitter bismuth-213 (Bi) and HER2-targeting sdAbs. The specificity, affinity, and cytotoxic potency of the radiolabeled complex were analyzed on HER2 cells. Its biodistribution through serial dissections and Cherenkov and micro-single-photon emission computed tomography (CT)/CT imaging was evaluated. Finally, the therapeutic efficacy and potential associated toxicity of [Bi]Bi-DTPA-2Rs15d were evaluated in a HER2 tumor model that manifests peritoneal metastasis. , [Bi]Bi-DTPA-2Rs15d bound HER2 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 [Bi]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 Bi, and after intravenous administration, revealing high 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 [Bi]Bi-DTPA-sdAb as a new radioconjugate for TAT, alone and as an add-on to trastuzumab for the treatment of HER2 metastatic cancer.
对于HER2阳性转移性癌症，靶向α粒子疗法（TAT）可能是一种克服对传统疗法耐药性的相关治疗策略。单域抗体片段（sdAb）因其优异的特性、高靶向亲和力和快速清除动力学，有望成为TAT的载体。本研究将细胞毒性α粒子发射体铋-213（Bi）与靶向HER2的sdAb相结合。对HER2细胞分析了放射性标记复合物的特异性、亲和力和细胞毒性效力。通过连续解剖以及切伦科夫和微单光子发射计算机断层扫描（CT）/CT成像评估了其生物分布。最后，在表现出腹膜转移的HER2肿瘤模型中评估了[Bi]Bi-DTPA-2Rs15d的治疗效果和潜在相关毒性。[Bi]Bi-DTPA-2Rs15d以HER2特异性方式结合HER2细胞。在小鼠中，注射后15分钟肿瘤摄取就已达到高水平，而在正常组织中观察到极低的摄取值。同时输注琥珀酰明胶可使肾脏摄取降低2倍。单独给予[Bi]Bi-DTPA-2Rs15d以及与曲妥珠单抗联合使用均导致中位生存期显著延长。我们首次描述了用α发射体Bi成功标记HER2-sdAb，静脉注射后，其在靶组织中显示出高稳定性和特异性蓄积，并导致这些小鼠的中位生存期延长，尤其是与曲妥珠单抗联合使用时。这些结果表明[Bi]Bi-DTPA-sdAb作为一种新的放射性缀合物用于TAT的潜力，单独使用以及作为曲妥珠单抗的附加药物用于治疗HER2转移性癌症。
