RT Journal Article
SR Electronic
T1 Melanocortin 1 Receptor–Targeted α-Particle Therapy for Metastatic Uveal Melanoma
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1124
OP 1133
DO 10.2967/jnumed.118.217240
VO 60
IS 8
A1 Narges K. Tafreshi
A1 Christopher J. Tichacek
A1 Darpan N. Pandya
A1 Michael L. Doligalski
A1 Mikalai M. Budzevich
A1 HyunJoo Kil
A1 Nikunj B. Bhatt
A1 Nancy D. Kock
A1 Jane L. Messina
A1 Epifanio E. Ruiz
A1 Nella C. Delva
A1 Adam Weaver
A1 William R. Gibbons
A1 David C. Boulware
A1 Nikhil I. Khushalani
A1 Ghassan El-Haddad
A1 Pierre L. Triozzi
A1 Eduardo G. Moros
A1 Mark L. McLaughlin
A1 Thaddeus J. Wadas
A1 David L. Morse
YR 2019
UL http://jnm.snmjournals.org/content/60/8/1124.abstract
AB 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.