Preclinical safety and effectiveness of a long-acting somatostatin analogue [²²⁵Ac]Ac-EBTATE against small cell lung cancer and pancreatic neuroendocrine tumors.

Abstract

We report the preclinical evaluation of potent long-acting [²²⁵Ac]Ac-EBTATE against SSTR2-positive small cell lung cancer (SCLC) and pancreatic neuroendocrine tumors (pan-NETs). The pharmacokinetic, biodistribution, and safety studies were evaluated in healthy female and/or male BALB/c mice after intravenous injections of [²²⁵Ac]Ac-EBTATE. Further biodistribution and radioligand therapy were investigated in female athymic BALB/c nude mice bearing high or low SSTR2-expressing subcutaneous SCLC models NCI-H524 or NCI-H727, respectively, and in a pan-NET model QGP1.SSTR2. Pharmacokinetics confirmed a prolonged clearance half-life (40.27 ± 9.23 h) while biodistribution in healthy male and female BALB/c mice was similar, with prolonged blood circulation that peaked at 6 h. Biodistribution in subcutaneous xenograft models of NCI-H524 and NCI-H727 showed consistent tumor-uptake with SSTR2-overexpression while the projected human effective doses for males and females were 61.7 and 83.7 millisievert/megabecquerel, respectively. 2 × 34 kBq of [²²⁵Ac]Ac-EBTATE administered 10 days (d) apart, was generally tolerated for 28 days in healthy BALB/c mice as revealed by blood biochemistry, complete blood count, and histopathological examination of H&E-stained organs. Targeted alpha therapy at 2 × 30 kBq of [²²⁵Ac]Ac-EBTATE, injected 10 days apart, resulted in 100% survivals and 80% and 20% complete remissions for NCI-H524 and QGP1.SSTR2 models, respectively. Additionally, [²²⁵Ac]Ac-EBTATE had a dose-dependent response in the NCI-H727 model, with median survivals for 2 × 30 kBq and 2 × 15 kBq groups being 63 d (p < 0.0007), and 47 d (p = 0.0148), respectively. [²²⁵Ac]Ac-EBTATE is safe and effective against SCLC and pan-NET and therefore warrants clinical investigation.