Preclinical evaluation of a novel radioligand therapy for patients with prostate cancer: biodistribution and efficacy of 177Lu-rhPSMA-10.1 in comparison with 177Lu-PSMA-I&T

Introduction: Theranostic radiohybrid prostate-specific membrane antigen (rhPSMA) ligands offer the potential for ¹⁸F-radiolabeling for use in diagnostic imaging or to be labeled with alpha- or beta-emitting radiometals for systemic radiation therapy. Novel rhPSMA radiopharmaceutical, ¹⁷⁷Lu-rhPSMA-10.1, is in development as a potential therapeutic agent for prostate cancer. Here, we present data from preclinical analyses evaluating its biodistribution and therapeutic efficacy in comparison with ¹⁷⁷Lu-PSMA-I&T.

Methods: To explore the longitudinal biodistribution of ¹⁷⁷Lu-rhPSMA-10.1 and ¹⁷⁷Lu-PSMA-I&T in non-tumor-bearing BALB/c mice, the tissues of interest were harvested for radioactivity measurement, 1, 12, 24, 48 and 168 h after intravenous injection of 1 MBq of either radiopharmaceutical (4 mice per timepoint).

The 22Rv1 prostate cancer xenograft mouse model (expressing relatively low PSMA levels) was used to determine the tumor:kidney uptake ratio of both compounds in a further, single-timepoint, biodistribution analysis. 1 MBq of either radiopharmaceutical was administered intravenously to 22Rv1 tumor-bearing SCID mice (n=4 for ¹⁷⁷Lu-rhPSMA-10.1, n=3 for ¹⁷⁷Lu-PSMA-I&T) 15 h prior to tissue harvesting.

The efficacy of ¹⁷⁷Lu-rhPSMA-10.1 and ¹⁷⁷Lu-PSMA-I&T was compared in 22Rv1 tumor-bearing NMRI nu/nu mice (n=8 per group). Tumor volume and body weight were measured twice a week for 35 d following a single intravenous injection of vehicle, either of the non-radiolabeled PSMA compounds, or either of the ¹⁷⁷Lu-radiolabeled PSMA compounds (30 MBq). Blood was collected on study days -1, 14 and 28 for hematological assessment.

Results: As presented in Table 1, the longitudinal biodistribution analysis showed that ¹⁷⁷Lu-rhPSMA-10.1 was rapidly cleared from the blood. Significant kidney uptake was evident for both ¹⁷⁷Lu-rhPSMA-10.1 and ¹⁷⁷Lu-PSMA-I&T, with eventual clearance from the kidneys over the study period. Kidney retention was markedly lower for ¹⁷⁷Lu-rhPSMA-10.1 than ¹⁷⁷Lu-PSMA-I&T at all timepoints, with 6.5-fold lower levels of ¹⁷⁷Lu-rhPSMA-10.1 observed at the 12 h timepoint. No other organ (including the brain) showed any significant uptake of ¹⁷⁷Lu-rhPSMA-10.1.

The 22Rv1 prostate tumor xenograft model also showed lower kidney uptake of ¹⁷⁷Lu-rhPSMA-10.1. Kidney uptake was 6.4-fold lower for ¹⁷⁷Lu-rhPSMA-10.1 than for ¹⁷⁷Lu-PSMA-I&T 15 h post-injection. Furthermore, higher tumor uptake was seen with ¹⁷⁷Lu-rhPSMA-10.1 than ¹⁷⁷Lu-PSMA-I&T at this timepoint, resulting in an improved tumor:kidney ratio for ¹⁷⁷Lu-rhPSMA-10.1 (Fig 1).

The efficacy analyses showed that 35 d after treatment the mean tumor volume was significantly reduced by ¹⁷⁷Lu-rhPSMA-10.1 compared with vehicle control (p=0.045, one-way analysis of variance, Fig 2). Moreover, when measuring fold-change in tumor volume relative to volume at inclusion, ¹⁷⁷Lu-rhPSMA-10.1 showed a statistically significant suppression of tumor growth compared to both non-radiolabeled rhPSMA-10.1 and vehicle control at both Study Day 14 (p<0.01 both comparisons) and at Day 35 (p<0.01 vs non-radiolabeled rhPSMA-10.1 and p<0.001 vs vehicle). ¹⁷⁷Lu-PSMA-I&T also reduced tumor growth compared with vehicle control (p<0.05), but to a lesser extent than ¹⁷⁷Lu-rhPSMA-10.1. No significant effects were noted on any hematological parameters or body weight.

Conclusions: This series of preclinical analyses show ¹⁷⁷Lu-rhPSMA-10.1 performed favorably compared with ¹⁷⁷Lu-PSMA-I&T, with a markedly improved tumor:kidney uptake ratio. ¹⁷⁷Lu-rhPSMA-10.1 significantly suppressed tumor growth relative to control, and to a greater extent than ¹⁷⁷Lu-PSMA-I&T.

The favorable renal clearance of ¹⁷⁷Lu-rhPSMA-10.1 has since been confirmed in a minipig model that may be more representative of human physiology, and ¹⁷⁷Lu-rhPSMA-10.1 is entering clinical trials in 2022.

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