Preliminary evaluation of a novel PSMA-targeting radiopharmaceutical [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-NYM032 for theranostic use in prostate cancer.

Abstract

A novel theranostic radiopharmaceutical targeting prostate-specific membrane antigen (PSMA), [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-NYM032, was developed and its diagnostic and therapeutic potential in the treatment of prostate cancer (PCa) was preliminarily evaluated. The diagnostic efficacy of the PET tracer [⁶⁸Ga]Ga-NYM032 was first evaluated in PSMA-positive xenograft-bearing models (LNCaP models), followed by evaluation in 10 PCa patients using [⁶⁸Ga]Ga-PSMA617 a comparator. Finally, the therapeutic potential of [¹⁷⁷Lu]Lu-NYM032 was evaluated in LNCaP models. [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-NYM032 was well-tolerated, and no adverse events were observed in the preclinical and clinical studies. [⁶⁸Ga]Ga-NYM032 demonstrated PSMA specificity and high radioactive uptake in LNCaP tumors. [⁶⁸Ga]Ga-NYM032 uptake (SUV_max) did not differ from [⁶⁸Ga]Ga-PSMA617 uptake in the same in situ lesions at the same p.i. time point (median 9.40 vs. 6.85, P = 0.123, n = 8). Compared with [⁶⁸Ga]Ga-PSMA617 uptake, [⁶⁸Ga]Ga-NYM032 uptake was significantly higher in osseous metastases (median 5.10 vs. 3.88, P < 0.001, n = 48), and higher in lymph node metastases (median 7.81 vs. 5.46, n = 2). [¹⁷⁷Lu]Lu-NYM032 showed high aggregation in the lesions of LNCaP models and long retention times. [¹⁷⁷Lu]Lu-NYM032 could inhibit tumor progression in LNCaP models, and its therapeutic efficiency strengthened with increasing radio-dosage (18.5-74 MBq/mouse). The tumor volume in the high radio-dosage treatment group (74 MBq/mouse) was significantly smaller than that in the blank control group at 21 days p.i. (107.14 ± 13.68 mm³ vs. 1351.86 ± 249.98 mm³, P < 0.001, n = 7). [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-NYM032 has considerable potential as a novel and powerful theranostic radiopharmaceutical for PCa. The clinical evaluation of this study was registered at Clinicaltrial.gov (NCT06389695) on 29 Apr, 2024.