Actinium-225-rhPSMA-10.1 as a novel, alpha-particle-emitting therapy for prostate cancer: results of a preclinical evaluation

Background Novel, radiohybrid, beta-particle-emitting, PSMA-targeted radiopharmaceutical therapy [ 177 Lu]Lu-rhPSMA-10.1 shows promising preclinical and clinical efficacy in prostate cancer. Here, we evaluated [ 225 Ac]Ac-rhPSMA-10.1 as a potential alpha-particle-emitting, PSMA-targeted radiopharmaceutical therapy for prostate cancer. Methods Lipophilicity of [ 225 Ac]Ac-rhPSMA-10.1 and [ 177 Lu]Lu-rhPSMA-10.1 (0.1-0.3 MBq) was assessed by shake-flask method. PSMA-binding affinity (IC 50 ) was evaluated in a competitive binding assay using rhPSMA-10.1 complexed with natural Lanthanum ([ nat La]; non-radioactive [ 225 Ac]Ac surrogate) or natural Lutetium ([ nat Lu]) in PSMA-expressing LNCaP cells. Cellular internalization (normalized to that of [ 177 Lu]Lu-PSMA-I&T) was assessed after 1-hour incubation of LNCaP cells (5x10 5 cells in 1 mL/well) with [ 225 Ac]Ac-rhPSMA-10.1 or [ 177 Lu]Lu-rhPSMA-10.1. In vivo assessments were conducted using PSMA-expressing 22Rv1 prostate cancer xenografts (eight mice/group plus untreated controls). Efficacy (tumour growth and survival) versus controls was assessed ≤49 days after a single-dose of [ 225 Ac]Ac-rhPSMA-10.1 (30 KBq) or [ 177 Lu]Lu-rhPSMA-10.1 (30 MBq). Tolerability was evaluated by bodyweight monitoring. Results [ 225 Ac]Ac-rhPSMA-10.1 and [ 177 Lu]Lu-rhPSMA-10.1 showed similar in vitro profiles: low lipophilicity (log D oct/PBS pH 7.4 = -3.4 ± 0.2 and log D oct/PBS pH 7.4 = -3.8 ± 0.1, respectively), high PSMA binding affinity ([ nat La]La-rhPSMA-10.1 IC 50 = 3.6 ± 0.6 nM, [ nat Lu]Lu-rhPSMA-10.1 IC 50 = 1.6 ± 0.1 nM) and high internalization (99% ± 14 and 108% ± 5, respectively). In vivo , [ 225 Ac]Ac-rhPSMA-10.1 significantly reduced tumour growth versus controls from Day 14-31 ( p < 0.05), and significantly prolonged median survival (43.5 days) versus controls (27.0 days; p = 0.006). There were no significant differences in tumour growth suppression or survival between the radiopharmaceuticals, and both were well tolerated. Conclusion [ 225 Ac]Ac-rhPSMA-10.1 displayed similar in vivo properties to [ 177 Lu]Lu-rhPSMA-10.1 and similar efficacy in prostate cancer xenografts at lower administered radioactivity.