Preclinical evaluation of ²²⁵Ac-labeled minigastrin analog DOTA-CCK-66 for Targeted Alpha Therapy

Abstract: The recently developed metabolically more stable minigastrin derivative, DOTA-CCK-66, displayed promising preclinical data when labeled either with ⁶⁸Ga or ¹⁷⁷Lu. First positron emission tomography/computed tomography (PET/CT) imaging using [⁶⁸Ga]Ga-DOTA-CCK-66 in two patients suffering from medullary thyroid carcinoma (MTC) displayed a favorable biodistribution profile. Here, we aim to investigate the therapeutic potential of [²²⁵Ac]Ac-DOTA-CCK-66 as a targeted α-therapy (TAT) agent in a comparative treatment study of [¹⁷⁷Lu]Lu- versus [²²⁵Ac]Ac-DOTA-CCK-66. Methods: Treatment studies were performed (3 groups, n = 5, AR42J tumor-bearing 394-NOD SCID mice). Control group animals were injected with [⁶⁸Ga]Ga-DOTA-CCK-66 (1.1 MBq, PET/CT imaging), while treatment group animals received a single dose of either [¹⁷⁷Lu]Lu-DOTA-CCK-66 (37 MBq, radioligand therapy (RLT)) or [²²⁵Ac]Ac-DOTA-CCK-66 (37 kBq, TAT). All animals' tumor volume and body weight were monitored twice a week until end-point criteria were reached. Blood samples were evaluated (VetScan VS2, Abaxis) once mice were sacrificed. Results: Upon treatment, an initial decline in tumor volume, followed by a significantly delayed tumor growth of treated cohorts, was observed. Mean survival of ¹⁷⁷Lu- as well as ²²⁵Ac-treated animals was increased by 3- (37 ± 3 d) and 4.5-fold (54 ± 6 d), respectively, when compared to non-treated animals (12 ± 3 d). Blood sample analysis did not indicate toxic side effects to the liver, kidney, or stomach upon ¹⁷⁷Lu and ²²⁵Ac-treatment. Conclusion: We demonstrated a substantial therapeutic efficacy of ¹⁷⁷Lu- and ²²⁵Ac-labeled DOTA-CCK-66. As expected, treatment with the latter resulted in the highest mean survival rates. These results indicate a high therapeutic potential of ²²⁵Ac-labeled DOTA-CCK-66 for TAT in MTC patient management. Graphical abstract: (Figure presented.)