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

Abstract

Introduction: [177Lu]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 [177Lu]Lu-PSMA-617 using [177Lu]Lu3+ produced via 176Lu(n,γ)177Lu route with moderate specific activity (0.66-0.81 GBq/μg). Methods: [177Lu]Lu-PSMA-617 was synthesized using moderate specific activity [177Lu]LuCl3 (0.74 GBq/μg) with PSMA-617 having metal-to-ligand molar ratio ∼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 [177Lu]Lu-PSMA-617 for adopting in a hospital radiopharmacy setting. Although the radiochemical yield of [177Lu]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 [177Lu]Lu-PSMA-617 was retained up to 72 and 120 h after radiolabeling and upon storage at -20°C with a radioactive concentration between 0.37 and 0.74 GBq/mL upon using stabilizer concentration as low as 43-48 μg/mCi. Preclinical cell-binding studies of [177Lu]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 ∼1.5-2.0 cm3 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 [177Lu]Lu-PSMA-617 in the tumor region. Conclusions: Formulation of a ready-to-use multidose formulation of [177Lu]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 [177Lu]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.

• Authors: Avik Chakraborty, Arpit Mitra, Megha Tawate, Sudip Sahoo, Sangita Lad, Sutapa Rakshit, Sujay Gaikwad, Sandip Basu, Hemant Shimpi, Sharmila Banerjee
• Journal: Cancer biotherapy & radiopharmaceuticals (Cancer Biother Radiopharm) Vol. 36 Issue 8 Pg. 682-692 (Oct 2021) ISSN: 1557-8852 [Electronic] United States
• PMID: 34402687 (Publication Type: Journal Article)

Chemical References

• Antigens, Surface
• Dipeptides
• Heterocyclic Compounds, 1-Ring
• PSMA-617
• Radioisotopes
• Radiopharmaceuticals
• Lutetium
• Lutetium-177
• FOLH1 protein, human
• Glutamate Carboxypeptidase II
• Prostate-Specific Antigen

Topics

• Animals
• Antigens, Surface
• Cell Line, Tumor
• Clinical Protocols
• Dipeptides (pharmacology)
• Dose-Response Relationship, Radiation
• Glutamate Carboxypeptidase II (antagonists & inhibitors)
• Heterocyclic Compounds, 1-Ring (pharmacology)
• Humans
• Lutetium (pharmacology)
• Male
• Mice
• Mice, Nude
• Neoplasm Metastasis (radiotherapy)
• Prostate-Specific Antigen (pharmacology)
• Prostatic Neoplasms, Castration-Resistant (pathology, radiotherapy)
• Radioisotopes (pharmacology)
• Radiopharmaceuticals (pharmacology)
• Radiotherapy Dosage
• Tissue Distribution
• Xenograft Model Antitumor Assays