Abstract 5198: Targeted alpha particle therapy for uveal melanoma
Authors: Tafreshi Narges K. , Delva Nella C. , Tichacek Christopher J. , Doligalski Michael L. , Pandya Darpan N. , Bhatt Nikunj B. , Kil HyunJoo , Budzevich Mikalai M. , Ruiz Epifanio , Wadas Thaddeus J. , McLaughlin Mark L. , Morse David L. 
Published: July 2017

New effective therapies are greatly needed for uveal melanoma, the most common ocular malignancy, which has a very poor prognosis with a median survival of less than one year when metastatic disease develops. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanomas but is not expressed in normal tissues of concern for toxicity. Previously, we developed an MC1R specific ligand (MC1RL) with high affinity and selectivity for MC1R. We used the MC1RL as a targeting scaffold for development of a radiopharmaceutical by conjugation of 225Ac chelate to form 225Ac -MC1RL-DOTA. 225Ac is a therapeutic alpha-emitting radionuclide. 225Ac -MC1RL-DOTA was synthesized with high radiochemical yield and purity (&gt;95 and &gt;99 % respectively) with an excellent in vitro stability, i.e. 90% after 10 days in human serum at 37ºC. An MTT cytotoxicity study demonstrated MC1R specific antiproliferative effect in cutaneous, ocular and uveal melanoma cell lines. A maximum tolerated dose (MTD) study was completed, where a range of 0-148 kBq (0-4 µCi) of 225Ac -MC1RL-DOTA was administered to groups of BALB/c mice. The radiopharmaceutical was well tolerated at even the highest doses and animals did not reach any clinical endpoints, such as weight loss, loss of kidney function or abnormal pathology. Biodistribution studies on MC1R expressing tumor bearing mice revealed tumor selectivity and a combination of renal and hepatic clearance with minimal retention in other normal tissues. A blood PK study in rats showed rapid clearance of the agent from the blood in &lt;60 min. To determine radiodosimetry, gamma spectra were acquired for tumors, blood and other tissues and organs over a 21-day time period and activity curves generated for each tissue for 225Ac and other gamma-emitting daughter products in the decay chain. An exponential line-fitting of these curves allowed the estimation of clearance kinetics, tissue biological half-life and total absorbed dose (Gy) for each tissue. Doses were highest in MC1R positive tumors and clearance organs (liver, kidney and spleen) and low in all other tissues. In vivo efficacy studies were performed in human A375/MC1R cutaneous and MEL20 uveal melanoma tumors in SCID mice, or syngeneic mouse B16 melanoma tumors in C57BL/6 mice (n=10/group) injected with either 225Ac -MC1RL-DOTA, 225Ac-scrambled-MC1RL-DOTA, La-MC1RL-DOTA (non-radioactive control agent) or saline. In every case a tumor growth delay was observed in treated mice relative to controls, and a percentage of mice bearing the human tumors had complete remission. In conclusion, we evaluated the in vitro and in vivo properties of 225Ac-MC1RL-DOTA in this study. This agent demonstrated a significant MC1R-specific in vivo therapeutic efficacy in a mouse model of uveal melanoma with low systemic toxicity.

Citation Format: Narges K. Tafreshi, Nella C. Delva, Christopher J. Tichacek, Michael L. Doligalski, Darpan N. Pandya, Nikunj B. Bhatt, HyunJoo Kil, Mikalai M. Budzevich, Epifanio Ruiz, Thaddeus J. Wadas, Mark L. McLaughlin, David L. Morse. Targeted alpha particle therapy for uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5198. doi:10.1158/1538-7445.AM2017-5198