Therapeutic Multidose Preparation of a Ready-to-Use Lu-177-PSMA-617 Using Carrier Added Lutetium-177 in a Hospital Radiopharmacy and Its Clinical Efficacy

Introduction: [Lu-177]Lu-prostate-specific membrane antigen (PSMA)-617 has emerged as a promising radiopharmaceutical for targeting PSMA in metastatic castrate-resistant prostate carcinoma (mCRPC). We have optimized the radiolabeling protocol for a multidose formulation (27-28.8 GBq equivalent to 6-7 patient-doses) of [Lu-177]Lu-PSMA-617 using [Lu-177]Lu3+ produced via Lu-176(n,gamma)Lu-177 route with moderate specific activity (0.66-0.81 GBq/mu g). Methods: [Lu-177]Lu-PSMA-617 was synthesized using moderate specific activity [Lu-177]LuCl3 (0.74 GBq/mu g) with PSMA-617 having metal-to-ligand molar ratio similar to 1: 2.5 in CH3COONH4 buffer (0.1 M) containing gentisic acid at pH 4.0-4.5. Human prostate carcinoma cell line LNCaP cell (high PSMA expression) was used for in vitro cell-binding studies and generating tumor xenograft models in nude mice for tissue biodistribution studies. Several batches of the present formulation have been clinically administered in mCRPC patients (single patient dose: 4.44-5.55 GBq per cycle). Results: In this study we report a consistent and reproducible protocol for multidose formulations of [Lu-177]Lu-PSMA-617 for adopting in a hospital radiopharmacy setting. Although the radiochemical yield of [Lu-177]Lu-PSMA-617 was found to be 97.30% +/- 1.03%, the radiochemical purity was 98.24% +/- 0.50% (n = 19). In vitro and serum stability of [Lu-177]Lu-PSMA-617 was retained up to 72 and 120 h after radiolabeling and upon storage at -20 degrees C with a radioactive concentration between 0.37 and 0.74 GBq/mL upon using stabilizer concentration as low as 43-48 mu g/mCi. Preclinical cell-binding studies of [Lu-177]Lu-PSMA-617 revealed specific binding with LNCaP cells of 17.4% +/- 2.4%. The uptake in LnCaP xenografted tumor (nude mice) was 7.5 +/- 2.6% ID/g for similar to 1.5-2.0 cm(3) tumor volume at 24-h post-injection. Post-therapy (24 h) SPECT image of mCRPC patients with prior orchidectomy and various hormone therapy showed specific localization of [Lu-177]Lu-PSMA-617 in the tumor region. Conclusions: Formulation of a ready-to-use multidose formulation of [Lu-177]Lu-PSMA-617 was successfully achieved and the procedure was optimized for routine preparation at a hospital radiopharmacy set-up. High degree of localization of [Lu-177]Lu-PSMA-617 in post-therapy SPECT scan and the post-therapeutic response confirms its therapeutic efficacy. Clinical Trials.gov ID: RPC/51/Minutes/Final dated 16th October, 2019.