Abstract 583: Preclinical development of [68Ga]Ga/[225Ac]Ac-FL-031 theranostic pair for the treatment of SSTR2-positive cancers

Abstract Somatostatin receptor 2 (SSTR2) is frequently overexpressed in solid tumors including neuroendocrine tumors (NETs) and small cell lung cancer (SCLC), making it a promising target for radionuclide drug conjugates (RDC) based cancer imaging and therapy. Gallium-68 and Lutetium-177 labeled somatostatin analogs [68Ga]Ga/[177Lu]Lu-DOTATATE, a theranostic pair, have been approved by FDA for detecting and treating gastroenteropancreatic (GEP)-NETs. Currently, [225Ac]Ac-DOTATATE is under clinical development for the treatment of SSTR2-positive cancers. To further optimize the theranostic profile of SSTR2-targeting RDC, we have applied our proprietary UniRDCTM platform technologies to discover FL-031, a novel and potentially next generation SSTR2-targeting RDC vector. We then evaluated the feasibility of PET/CT imaging with [68Ga]Ga-FL-031, as well as the in vivo biodistribution and efficacy profiles of [225Ac]Ac-FL-031 in SSTR2+ xenograft mouse models. The radiochemical purity (RCP) of radiolabeled FL-031 was determined by radio high-performance liquid chromatography (radio-HPLC). FL-031 was successfully labeled with 68Ga and 225Ac, achieving an RCP of over 98% and specific activities of 18.5 MBq/nmol and 185 kBq/nmol, respectively. Subsequently, PET/CT imaging and in vivo biodistribution as well as efficacy was conducted in SSTR2-expressing SCLC and NET tumor-xenograft models. After administration of 3.7 MBq [68Ga]Ga -FL-031 in mice implanted with SCLC-21H SCLC xenografts, PET/CT images demonstrated intense tumor uptake which was significantly higher than in normal organs at 1- and 3-hour post-dosing. In the in vivo biodistribution study, [225Ac]Ac-FL-031 showed high and durable tumor uptake in mice implanted with AR42J NET xenografts with fast clearance in normal organs. Importantly, in SSTR2+ xenograft models, [225Ac]Ac-FL-031 exhibited significant anti-tumor activity at dose levels of 37 kBq or lower without notable changes in body weight and hematology parameters. In summary, [68Ga]Ga-FL-031 PEC/CT proved suitable in detecting SSTR2-positive tumors in preclinical models. [225Ac]Ac-FL-031 demonstrated a promising in vivo biodistribution profile and anti-tumor activity in SSTR2-expressing xenograft models. In conclusion, our data suggest that [68Ga]Ga/[225Ac]Ac-FL-031 is a promising theranostic pair for further development as a diagnostic imaging and RDC therapy for SSTR2-positive cancers. Citation Format: Junyu Yang, Taishan Hu, Lanjiao Zhao, Yihu Xie, Juan Zhang, Fa Liu. Preclinical development of [68Ga]Ga/[225Ac]Ac-FL-031 theranostic pair for the treatment of SSTR2-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 583.