Pretargeted alpha radioimmunotherapy (DOTA-PRIT) for HER2-expressing human gastric cancer: a theranostic approach using 111In/225Ac-radiohapten.

摘要: 288 Objectives: We have reported CRs and cures using anti-HER2/anti-DOTA hapten bispecific pretargeted radioimmunotherapy (anti-HER2-DOTA-PRIT) approach for treatment of HER2-expressing breast cancer beta- or alpha-emitting isotopes. As part this work, we documented identical pharmacodynamics the theranostic pairs: In-111- versus Ac-225 - radiohapten chelates (proteus DOTA, PrDOTA; Mol Imaging Biol 2019 21: 167-335). Herein report on an extension our studies to a second solid tumor NCI-N87 gastric mouse model. Methods: Initial biodistribution (using In-111) therapy Ac-225) were performed in groups nude mice bearing subcutaneous (s.c.) HER2-positive (HER2(+)) human carcinoma xenografts (5 x 106 cells/mouse; initiated day 14 post-inoculation). The anti-HER2-DOTA-PRIT targeting regimen was administered intravenously (i.v.): 0.25 mg (1.19 nmol) anti-HER2-C825 at t = -28 hours (h), 25 µg CCA16-DOTAY clearing agent (2.76 -4 h, [111In]PrDOTA [225Ac]PrDOTA 0 h. A study 24 h post-injection (n 5, 24-26 µCi (888-962 kBq), 120-130 pmol). separate preliminary with one two cycles (0.74-0.79 nmol, 1 (37 kBq)) appropriate controls (no treatment, only, non-specific-DOTA-PRIT anti-GPA33 huA33-C825 place anti-HER2-C825). Survival characterized Kaplan-Meier curves, comparison log-rank test (significance: P Results: Biodistribution therapeutic surrogate 111In-radiolabeled proteus-DOTA (as mimic [225Ac]PrDOTA) 111In-activity showed tumor, blood, kidney uptakes 9.32 ± 1.25 % injected activity per gram (%IA/g), 1.14 0.33 %IA/g, 0.90 0.13 respectively. With regard alpha-DOTA-PRIT, all treatments well tolerated, noweight loss >10%. Anti-HER2-DOTA-PRIT highly efficacious shrinkage extended survival compared controls. Except 3/10 non-specific-DOTA-PRIT, died by 86 d progression. In contrast, treated group, as post treatment-initiation, 9/10 each group either still alive, volumes 444 170 mm3 154 93 single-cycle double-cycle respectively (significance greater effectiveness single vs. double cycle, 0.0002). No complete responses (CR; volume ≤10 mm3) observed anti-HER2-DOTA-PRIT, anti-HER2-DOTA-PRIT. Furthermore, median (MS; days (d) after initiation, defined time progression 1000 death any reason) 30 d, 36 56 no non-radioactive controls, Survivors will be evaluated status long-term toxicity 20 weeks. Conclusions: Alpha-DOTA-PRIT HER2 antigen, based Indium-111 radiohapten, achieves substantial tumors, is well-tolerated effective HER2(+) models, leading significantly prolonged (P ≤ 0.0043 anti-HER2-DOTA-PRIT). deaths from toxicity, dose escalation continue goal achieving 100% CR’s histologic preclinical models cancer.