Journal
JOURNAL OF NUCLEAR MEDICINE
Volume 60, Issue 8, Pages 1124-1133Publisher
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.118.217240
Keywords
melanocortin 1 receptor; Ac-225 alpha therapy; uveal melanoma; mouse model
Funding
- Miles for Moffitt Milestone Award
- Moffitt Imaging and Technology Center of Excellence
- NIH/NCI-Moffitt Skin Cancer SPORE [P50CA168536-03]
- Career Enhancement Program award
- NIH/NCI SBIR Phase 1 Contract to Modulation Therapeutics, Inc.
- Melanoma Research Alliance Team Science Award
- Analytic Microscopy, Bioinformatics and Biostatistics, Molecular Genomics, Proteomics, Small Animal Imaging Laboratory, and Tissue Core Facilities at the H. Lee Moffitt Cancer Center
- Research Institute, an NCI-designated Comprehensive Cancer Center [P30-CA076292]
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New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R-specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. Methods: The Ac-225-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-DOTA-MC1RL analog was tested for binding affinity. Non-tumor-bearing BALB/c mice were tested for maximum tolerated dose and biodistribution. Severe combined immunodeficient mice bearing uveal melanoma tumors or engineered MC1R-positive and -negative tumors were studied for biodistribution and efficacy. Radiation dosimetry was calculated using mouse biodistribution data and blood clearance kinetics from Sprague-Dawley rat data. Results: High biostability, MC1R-specific cytotoxicity, and high binding affinity were observed. Limiting toxicities were not observed at even the highest administered activities. Pharmacokinetics and biodistribution studies revealed rapid blood clearance (< 15 min), renal and hepatobillary excretion, MC1R-specific tumor uptake, and minimal retention in other normal tissues. Radiation dosimetry calculations determined pharmacokinetics parameters and absorbed alpha-emission dosages from Ac-225 and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden after a single administration of Ac-225-DOTAMC1RL in treated mice relative to controls. Conclusion: These results suggest significant potential for the clinical translation of Ac-225-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.
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