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

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.

[1]  C. Kratochwil,et al.  An Overview of Targeted Alpha Therapy with 225Actinium and 213Bismuth , 2018, Current radiopharmaceuticals.

[2]  Justin J. Wilson,et al.  Actinium-225 for Targeted α Therapy: Coordination Chemistry and Current Chelation Approaches. , 2018, Cancer biotherapy & radiopharmaceuticals.

[3]  U. Haberkorn,et al.  Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control , 2018, The Journal of Nuclear Medicine.

[4]  F. M. Nortier,et al.  Alpha-Emitters and Targeted Alpha Therapy in Oncology: from Basic Science to Clinical Investigations , 2018, Targeted Oncology.

[5]  R. Carvajal,et al.  Immunotherapy for the Treatment of Uveal Melanoma: Current Status and Emerging Therapies , 2017, Current Oncology Reports.

[6]  S. Blinder,et al.  Multi-isotope SPECT imaging of the 225Ac decay chain: feasibility studies , 2017, Physics in medicine and biology.

[7]  H. Soyer,et al.  Skin Pigmentation Genetics for the Clinic , 2017, Dermatology.

[8]  W. Weichert,et al.  Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding , 2017, The Journal of Nuclear Medicine.

[9]  Richard D Carvajal,et al.  Uveal melanoma: epidemiology, etiology, and treatment of primary disease , 2017, Clinical ophthalmology.

[10]  J. Wargo,et al.  Uveal melanoma: From diagnosis to treatment and the science in between , 2016, Cancer.

[11]  King Li,et al.  Preliminary Therapy Evaluation of 225Ac-DOTA-c(RGDyK) Demonstrates that Cerenkov Radiation Derived from 225Ac Daughter Decay Can Be Detected by Optical Imaging for In Vivo Tumor Visualization , 2016, Theranostics.

[12]  J. Little,et al.  MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project , 2015, British Journal of Cancer.

[13]  V. Sondak,et al.  In vivo and in silico pharmacokinetics and biodistribution of a melanocortin receptor 1 targeted agent in preclinical models of melanoma. , 2013, Molecular pharmaceutics.

[14]  James Inglese,et al.  Authentication of Human Cell Lines by STR DNA Profiling Analysis -- Assay Guidance Manual , 2013 .

[15]  M. Brechbiel,et al.  Molecular Pathways: Targeted α-Particle Radiation Therapy , 2012, Clinical Cancer Research.

[16]  V. Sondak,et al.  Synthesis and characterization of a melanoma-targeted fluorescence imaging probe by conjugation of a melanocortin 1 receptor (MC1R) specific ligand. , 2012, Bioconjugate chemistry.

[17]  S. Woodman,et al.  Genetic and molecular characterization of uveal melanoma cell lines , 2012, Pigment cell & melanoma research.

[18]  R. Gillies,et al.  Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand. , 2011, Journal of medicinal chemistry.

[19]  Ying-kui Yang.  Structure, function and regulation of the melanocortin receptors. , 2011, European journal of pharmacology.

[20]  Ravy K. Vajravelu,et al.  Radioimmunotherapy of breast cancer metastases with alpha-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y. , 2009, Cancer research.

[21]  R. Senekowitsch-Schmidtke,et al.  Treatment of Peritoneal Carcinomatosis by Targeted Delivery of the Radio-Labeled Tumor Homing Peptide 213Bi-DTPA-[F3]2 into the Nucleus of Tumor Cells , 2009, PloS one.

[22]  Wesley E. Bolch,et al.  MIRD Pamphlet No. 21: A Generalized Schema for Radiopharmaceutical Dosimetry—Standardization of Nomenclature , 2009, Journal of Nuclear Medicine.

[23]  R. Senekowitsch-Schmidtke,et al.  Preclinical Evaluation of the α-Particle Generator Nuclide 225Ac for Somatostatin Receptor Radiotherapy of Neuroendocrine Tumors , 2008, Clinical Cancer Research.

[24]  S. Gambhir,et al.  64Cu-labeled alpha-melanocyte-stimulating hormone analog for microPET imaging of melanocortin 1 receptor expression. , 2007, Bioconjugate chemistry.

[25]  R. Kiessling,et al.  Melanocortin 1 receptor is expressed by uveal malignant melanoma and can be considered a new target for diagnosis and immunotherapy. , 2007, Investigative ophthalmology & visual science.

[26]  T. Nayak,et al.  Somatostatin-receptor-targeted α-emitting 213Bi is therapeutically more effective than β−-emitting 177Lu in human pancreatic adenocarcinoma cells , 2007 .

[27]  C. Apostolidis,et al.  Production of Ac-225 from Th-229 for targeted alpha therapy. , 2005, Analytical chemistry.

[28]  T. Quinn,et al.  Melanoma Therapy via Peptide-Targeted α-Radiation , 2005, Clinical Cancer Research.

[29]  M. Bonardi,et al.  How do we ascertain specific activities in no-carrier-added radionuclide preparations? , 2005 .

[30]  R. Gillies,et al.  Lanthanide-based time-resolved fluorescence of in cyto ligand-receptor interactions. , 2004, Analytical biochemistry.

[31]  O. Larsson,et al.  Tissue distribution and differential expression of melanocortin 1 receptor, a malignant melanoma marker , 2002, British Journal of Cancer.

[32]  D. Scheinberg,et al.  Tumor Therapy with Targeted Atomic Nanogenerators , 2001, Science.

[33]  D. Scheinberg,et al.  Breakthrough of 225Ac and its radionuclide daughters from an 225Ac/213Bi generator: development of new methods, quantitative characterization, and implications for clinical use. , 2001, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[34]  V. Chhajlani,et al.  Distribution of cDNA for melanocortin receptor subtypes in human tissues. , 1996, Biochemistry and molecular biology international.

[35]  Kratochwil Clemens,et al.  Targeted Alpha Therapy of mCRPC with 225Actinium-PSMA-617: Dosimetry estimate and empirical dose finding , 2017 .

[36]  G. Deblonde,et al.  Active actinium. , 2016, Nature chemistry.

[37]  V. Hruby,et al.  Fluorescent and lanthanide labeling for ligand screens, assays, and imaging. , 2011, Methods in molecular biology.

[38]  T. Nayak,et al.  Somatostatin-receptor-targeted alpha-emitting 213Bi is therapeutically more effective than beta(-)-emitting 177Lu in human pancreatic adenocarcinoma cells. , 2007, Nuclear medicine and biology.