Therapeutic Efficacy of ²¹³Bi-labeled sdAbs in a Preclinical Model of Ovarian Cancer

Abstract

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 <i>in vivo</i> properties, high target affinity, and fast clearance kinetics. This study combines the cytotoxic α-particle emitter bismuth-213 (²¹³Bi) and HER2-targeting sdAbs. The <i>in vitro</i> specificity, affinity, and cytotoxic potency of the radiolabeled complex were analyzed on HER2^pos cells. Its <i>in vivo</i> biodistribution through serial dissections and <i>via</i> 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. <i>In vitro</i>, [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 <i>in vivo</i> 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.