Journal Article

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

Babeker, Hanan, Gray, Brian D, Torlakovic, Emina E, Fonge, Humphrey, Pak, Koon Y, Njotu, Fabrice N, Nwangele, Emmanuel, Hassani, Nava, Pougoue Ketchemen, Jessica, Tikum, Anjong F, Henning, Nikita, Monzer, Alissar, Uppalapati, Maruti

2024

Overview

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).PURPOSEWe 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.METHODSThe 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.RESULTSPharmacokinetics 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.CONCLUSIONS[225Ac]Ac-EBTATE is safe and effective against SCLC and pan-NET and therefore warrants clinical investigation.