Preclinical Evaluation of 225Ac-Labeled Single-Domain Antibody for the Treatment of HER2pos Cancer

Abstract

Human epidermal growth factor receptor type 2 (HER2) is over- low accumulation in other organs (<1% IA/g) except for kidneys expressed in various cancers; thus, HER2-targeting single-domain (11.69 ± 1.10% IA/g). a-camera imaging presented homogeneous antibodies (sdAb) could offer a useful platform for radioimmunother- uptake of radioactivity in tumors, although heterogeneous in kidneys, apy. In this study, we optimized the labeling of an anti-HER2-sdAb with a higher signal density in cortex versus medulla. In mice with the a-particle-emitter 225Ac through a DOTA-derivative. The with HER2pos disseminated tumors, repeated administration of formed radioconjugate was tested for binding affinity, specificity and [225Ac]Ac-DOTA-2Rs15d significantly prolonged survival (143 days) internalization properties, whereas cytotoxicity was evaluated by compared to control groups (56 and 61 days) and to the group treated clonogenic and DNA double-strand-breaks assays. Biodistribution with HER2-targeting mAb trastuzumab (100 days). Histopathologic studies were performed in mice bearing subcutaneous HER2pos evaluation revealed signs of kidney toxicity after repeated administumors to estimate absorbed doses delivered to organs and tissues. tration of [225Ac]Ac-DOTA-2Rs15d. [225Ac]Ac-DOTA-2Rs15d effiTherapeutic efficacy and potential toxicity were assessed in HER2pos ciently targeted HER2pos cells and was effective in treatment of intraperitoneal ovarian cancer model and in healthy C57Bl/6 mice. intraperitoneal disseminated tumors, both alone and as an add-on [225Ac]Ac-DOTA-2Rs15d exhibited specific cell uptake and cell- combination with trastuzumab, albeit with substantial signs of killing capacity in HER2pos cells (EC50 ¼ 3.9 ± 1.1 kBq/mL). Uptake inflammation in kidneys. This study warrants further development in HER2pos lesions peaked at 3 hours (9.64 ± 1.69% IA/g), with very of [225Ac]Ac-DOTA-2Rs15d.