Melanocortin 1 Receptor-Targeted α-Particle Therapy for Metastatic Uveal Melanoma

Abstract

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 225Ac-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 α-emission dosages from 225Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden after a single administration of 225Ac-DOTA-MC1RL in treated mice relative to controls. Conclusion: These results suggest significant potential for the clinical translation of 225Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.

Keywords: 225Ac alpha therapy; melanocortin 1 receptor; mouse model; uveal melanoma.

© 2019 by the Society of Nuclear Medicine and Molecular Imaging.

Figures

FIGURE 1.

Radiochemical synthesis of 225Ac-DOTA-MC1RL.

FIGURE 2.

MTD study for non–tumor-bearing mice: percentage weight gain (A), blood urea nitrogen (B), and blood creatinine (C).

FIGURE 3.

Plot of rat blood clearance: exponential decay nonlinear regression line fit of 225Ac α-activity in rat blood over time, after intravenous administration of 225Ac-DOTA-MC1RL (n = 4 rats).

FIGURE 4.

Biodistribution of 225Ac-DOTA-MC1RL: 225Ac, 221Fr, and 213Bi activities in tissues from non–tumor-bearing BALB/c mice (n = 6 per time point) (A) and SCID mice bearing MEL270 human uveal melanoma tumors (n = 5 per time point) (B).

FIGURE 5.

Biodistribution of 225Ac-DOTA-MC1RL (A) and 225Ac-DOTA-SP (B) in bilateral A375 and A375/MC1R tumors (n = 5 per time point).

FIGURE 6.

Efficacy study in mice bearing MEL270 tumors: representative images of tumors (outlined) (A); initial tumor growth volumes (B); and Kaplan–Meier plots (C).

FIGURE 7.

Metastasis study in MEL270 uveal melanoma mouse model and MC1R expression in tumors reaching endpoints from each treatment group: representative hematoxylin and eosin staining and corresponding threshold segmentations of sections containing liver and lung metastases (cold = lanthanum-DOTA-MC1RL; scrambled = untargeted; treated = 225Ac-DOTA-MC1RL; blue = normal tissue; green = metastasis) (A); quantified metastasis burden (B); graph (C) and sections (D) for MC1R immunohistochemistry staining of MEL270 tumors after reaching endpoints.