Albumin-Binding PSMA Ligands: Implications for Expanding the Therapeutic Window.

Abstract

Despite significant gains in the treatment of metastatic castration-resistant prostate cancer by radioligands targeting prostate-specific membrane antigen (PSMA), 30% of patients never respond to therapy. One possible explanation is insufficient dose delivery to the tumor because of suboptimal pharmacokinetics. We have recently described RPS-063, a trifunctional ligand targeting PSMA with high uptake in LNCaP xenograft tumors but also in kidneys. We aimed to use structural modifications to increase the tumor-to-kidney ratio through increased albumin binding and tumor uptake and reduction of kidney activity. Methods: Four structurally related trifunctional PSMA-targeting small molecules were prepared by either varying the albumin-binding group or inserting a polyethylene glycol 8 linker into a common structure. The compounds were ranked by PSMA affinity and albumin affinity and were radiolabeled with 68Ga and 177Lu. Tissue kinetics were determined in male BALB/C nu/nu mice bearing LNCaP xenograft tumors. Results: Each of the compounds binds PSMA with a half-maximal inhibitory concentration of no more than 10 nM. The albumin-binding group had a minimal effect on PSMA affinity but changed albumin affinity by an order of magnitude. However, the addition of a polyethylene glycol 8 spacer weakened affinity for albumin in each case. Increased affinity for albumin corresponded with delayed blood clearance and modified uptake kinetics in the tumor and kidney. Uptake of 177Lu-RPS-072 (34.9 ± 2.4 %ID/g) and 177Lu-RPS-077 (27.4 ± 0.6 %ID/g) increased up to 24 h after injection, and washout by 96 h was not significant. As a result, the area under the curve (AUC) in the tumor was in the following order: 177Lu-RPS-072 > 177Lu-RPS-077 > 177Lu-RPS-063 > 177Lu-RPS-071. Increased linker length corresponded to more rapid clearance from kidneys. Consequently, the ratio of tumor AUC and kidney AUC was 4.7 ± 0.3 for 177Lu-RPS-072. Conclusion: The tumor AUC and tumor-to-kidney ratio of 177Lu-RPS-072 are significantly enhanced compared with any small molecule investigated in a LNCaP xenograft model to date. In comparison to other PSMA-targeting radioligands that have been evaluated in a PC3-PIP model, activity in kidneys is reduced and activity in tumors compares favorably when the different PSMA expression levels in LNCaP and PC3-PIP cells are considered. RPS-072 therefore exhibits an increased therapeutic index, shows the potential to increase the dose delivered to tumors, and is a highly promising candidate for targeted radioligand therapy.

• Authors: James M Kelly, Alejandro Amor-Coarasa, Shashikanth Ponnala, Anastasia Nikolopoulou, Clarence Williams Jr, Stephen G DiMagno, John W Babich
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 60 Issue 5 Pg. 656-663 (05 2019) ISSN: 1535-5667 [Electronic] United States
• PMID: 30552199 (Publication Type: Journal Article)
• Copyright: © 2019 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Albumins
• Antigens, Surface
• FOLH1 protein, human
• Glutamate Carboxypeptidase II

Topics

• Albumins (metabolism)
• Animals
• Antigens, Surface (metabolism)
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Glutamate Carboxypeptidase II (metabolism)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Positron Emission Tomography Computed Tomography
• Prostatic Neoplasms (diagnostic imaging, metabolism, pathology, radiotherapy)
• Radiochemistry
• Tissue Distribution
• Treatment Outcome