Preclinical Evaluation of¹⁷⁷Lu-rhPSMA-10.1, a Radiopharmaceutical for Prostate Cancer: Biodistribution and Therapeutic Efficacy

¹⁷⁷Lu-rhPSMA-10.1 is a novel radiohybrid prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy for prostate cancer. We conducted preclinical analyses on non-tumor-bearing BALB/c mice and on prostate cancer human xenograft mouse models (LNCAP and 22Rv1 xenografts) to evaluate its biodistribution and therapeutic efficacy. <b>Methods:</b> Longitudinal biodistribution of ¹⁷⁷Lu-rhPSMA-10.1 was evaluated in BALB/c mice and 22Rv1 xenografts. Tissues of interest were harvested, and radioactivity was measured 1-168 h after injection of 1 MBq of ¹⁷⁷Lu-rhPSMA-10.1 (4 per time point). Longitudinal biodistribution was compared with ¹⁷⁷Lu-PSMA-I&T (1 MBq) in BALB/c mice and at a single time point (15 h) in 22Rv1 xenografts. The therapeutic efficacy of a single administration of 15, 30, or 45 MBq of ¹⁷⁷Lu-rhPSMA-10.1 in LNCaP xenografts and 30 MBq of ¹⁷⁷Lu-rhPSMA-10.1, ¹⁷⁷Lu-PSMA-617, or ¹⁷⁷Lu-PSMA-I&T in 22Rv1 xenografts (8 per group) was evaluated. Efficacy versus vehicle was evaluated on the basis of relative tumor volume and survival up to 49 d after administration. Statistical significance was evaluated with <i>t</i> testing (biodistribution data), 2-way repeated-measures ANOVA (tumor volume [analyzed until 3 per group remained]), or Kaplan-Meier log-rank analyses (survival). <b>Results:</b> Biodistribution of ¹⁷⁷Lu-rhPSMA-10.1 in the BALB/c and 22Rv1 xenografts showed rapid clearance from blood and other normal tissues within 48 h, with the kidney showing the highest normal-organ uptake. Kidney uptake and retention were lower for ¹⁷⁷Lu-rhPSMA-10.1 than for ¹⁷⁷Lu-PSMA-I&T (6.5-fold lower at 12 h in BALB/c mice and 6.4-fold lower at 15 h in 22Rv1 xenografts; <i>P</i> < 0.01). High and sustained ¹⁷⁷Lu-rhPSMA-10.1 tumor uptake was observed in 22Rv1 xenografts. This uptake was 2.3-fold higher than that of ¹⁷⁷Lu-PSMA-I&T (15 h; <i>P</i> < 0.05). When efficacy was evaluated, ¹⁷⁷Lu-rhPSMA-10.1 significantly suppressed tumor growth versus vehicle from day 11 (<i>P</i> < 0.05) in LNCaP xenografts in a dose-dependent manner and from day 18 (<i>P</i> < 0.05) in 22Rv1 xenografts and significantly prolonged median survival versus vehicle in both models. In 22Rv1 xenografts, ¹⁷⁷Lu-rhPSMA-10.1 suppressed tumor growth versus vehicle to a greater extent than did ¹⁷⁷Lu-PSMA-I&T (significant growth inhibition from day 25 [<i>P</i> < 0.05]) and similarly in extent to ¹⁷⁷Lu-PSMA-617 (from day 18 [<i>P</i> < 0.05]). Overall, compared with ¹⁷⁷Lu-PSMA-I&T, ¹⁷⁷Lu-rhPSMA-10.1 suppressed tumor growth for longer than ¹⁷⁷Lu-PSMA-617 (inhibition from day 39 onward [<i>P</i> < 0.05] versus on day 49 only [<i>P</i> < 0.05]). <b>Conclusion:</b> In preclinical models, ¹⁷⁷Lu-rhPSMA-10.1 shows a favorable tumor-to-kidney uptake ratio, and significant antitumor effects, indicating it to be a promising next-generation radiopharmaceutical therapy.