JHU-2545 preferentially shields salivary glands and kidneys during PSMA-targeted imaging
Status Publisher Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články
Grantová podpora
R01CA161056
NCI NIH HHS - United States
R01CA201035
NCI NIH HHS - United States
R01CA229893
NCI NIH HHS - United States
R01CA240711
NCI NIH HHS - United States
RVO 61388963
IOCB
Programme EXCELES, ID Project No. LX22NPO5102
National Institute for Cancer Research
MII award
Maryland TEDCO
PubMed
39743616
DOI
10.1007/s00259-024-07044-7
PII: 10.1007/s00259-024-07044-7
Knihovny.cz E-zdroje
- Klíčová slova
- Kidneys, PSMA, Prostate cancer, Radioligand therapy, Salivary glands,
- Publikační typ
- časopisecké články MeSH
PURPOSE: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy. METHODS: A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment. RESULTS: JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers [68Ga]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor. CONCLUSIONS: JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.
Department of Neurology Johns Hopkins School of Medicine Baltimore MD 21205 USA
Department of Nuclear Medicine University Hospital Heidelberg Heidelberg Germany
Departments of Medicine Johns Hopkins School of Medicine Baltimore MD 21205 USA
Departments of Neuroscience Johns Hopkins School of Medicine Baltimore MD 21205 USA
Departments of Oncology Johns Hopkins School of Medicine Baltimore MD 21205 USA
Departments of Psychiatry Johns Hopkins School of Medicine Baltimore MD 21205 USA
Depatment of Radiology Washington University School of Medicine Saint Louis MO 63110 USA
Johns Hopkins Drug Discovery 855 North Wolfe Street Baltimore Maryland 21205 USA
Johns Hopkins Drug Discovery Johns Hopkins School of Medicine Baltimore MD 21205 USA
Zobrazit více v PubMed
Fendler WP, Rahbar K, Herrmann K, Kratochwil C, Eiber M. (177)Lu-PSMA Radioligand therapy for prostate Cancer. J Nucl Med. 2017;58:1196–200. PubMed DOI
Kratochwil C, Bruchertseifer F, Rathke H, et al. Targeted alpha-therapy of metastatic castration-resistant prostate Cancer with (225)Ac-PSMA-617: swimmer-plot analysis suggests Efficacy regarding duration of Tumor Control. J Nucl Med. 2018;59:795–802. PubMed DOI
von Eyben FE, Roviello G, Kiljunen T et al. Third-line treatment and (177)Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review. Eur J Nucl Med Mol Imaging. 2017.
Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate Cancer. N Engl J Med. 2021;385:1091–103. PubMed DOI PMC
Pluvicto (lutetium Lu. 177 vipivotide tetraxetan) [package insert]. Basel, Switzerland: Novartis AG; 2022.
Bouchelouche K, Turkbey B, Choyke PL. PSMA PET and Radionuclide Therapy in prostate Cancer. Semin Nucl Med. 2016;46:522–35. PubMed DOI PMC
Ristau BT, O’Keefe DS, Bacich DJ. The prostate-specific membrane antigen: lessons and current clinical implications from 20 years of research. Urol Oncol. 2014;32:272–9. PubMed DOI
Eiber M, Fendler WP, Rowe SP, Calais J, Hofman MS, Maurer T, et al. Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy. J Nucl Med. 2017;58:s67–76. DOI
Virgolini I, Decristoforo C, Haug A, Fanti S, Uprimny C. Current status of theranostics in prostate cancer. Eur J Nucl Med Mol Imaging. 2018;45:471–95. PubMed DOI
Afshar-Oromieh A, Babich JW, Kratochwil C, et al. The rise of PSMA ligands for diagnosis and therapy of prostate Cancer. J Nucl Med. 2016;57:s79–89. DOI
Kratochwil C, Giesel FL, Stefanova M, et al. PSMA-Targeted Radionuclide Therapy of Metastatic Castration-resistant prostate Cancer with 177Lu-Labeled PSMA-617. J Nucl Med. 2016;57:1170–6. PubMed DOI
AlSadi R, Bouhali O, Dewji S, Djekidel M. 177Lu-PSMA therapy for metastatic castration-resistant prostate Cancer: a Mini-review of State-of-the-art. Oncologist. 2022;27:e957–66. PubMed DOI PMC
Rahbar K, Ahmadzadehfar H, Kratochwil C, et al. German Multicenter Study investigating 177Lu-PSMA-617 Radioligand therapy in advanced prostate Cancer patients. J Nucl Med. 2017;58:85–90. PubMed DOI
Hofman MS, Violet J, Hicks RJ et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018.
O’Keefe DS, Bacich DJ, Heston WD. Comparative analysis of prostate-specific membrane antigen (PSMA) versus a prostate-specific membrane antigen-like gene. Prostate. 2004;58:200–10. PubMed DOI
Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997;3:81–5. PubMed
Taieb D, Foletti JM, Bardies M, Rocchi P, Hicks R, Haberkorn U. PSMA-Targeted Radionuclide Therapy and salivary gland toxicity: why does it matter? J Nucl Med. 2018.
Ling SW, de Blois E, Hooijman E, van der Veldt A, Brabander T. Advances in 177Lu-PSMA and 225Ac-PSMA Radionuclide Therapy for metastatic castration-resistant prostate Cancer. Pharmaceutics. 2022;14:2166. PubMed DOI PMC
Feurecker B, Tauber R, Knorr K, et al. Activity and adverse events of actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant prostate Cancer after failure of Lutetium-177-PSMA. Eur Urol. 2021;79:343–50. DOI
Kabasakal L, AbuQbeitah M, Aygun A, et al. Pre-therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42:1976–83. PubMed DOI
Kratochwil C, Giesel FL, Leotta K, et al. PMPA for nephroprotection in PSMA-targeted radionuclide therapy of prostate cancer. J Nucl Med. 2015;56:293–8. PubMed DOI
Zechmann CM, Afshar-Oromieh A, Armor T, et al. Radiation dosimetry and first therapy results with a (124)I/ (131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging. 2014;41:1280–92. PubMed DOI PMC
Kratochwil C, Bruchertseifer F, Rathke H et al. Targeted alpha therapy of mCRPC with 225Actinium-PSMA-617: Dosimetry estimate and empirical dose finding. J Nucl Med. 2017.
Chatalic KL, Heskamp S, Konijnenberg M, et al. Towards Personalized treatment of prostate Cancer: PSMA I&T, a promising prostate-specific membrane Antigen-targeted Theranostic Agent. Theranostics. 2016;6:849–61. PubMed DOI PMC
Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA-PET in prostate cancer management. Nat Rev Urol. 2016;13:226–35. PubMed DOI
Yordanova A, Becker A, Eppard E, et al. The impact of repeated cycles of radioligand therapy using [177Lu]Lu-PSMA-617 on renal function in patients with hormone refractory metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2017;44:1473–9. PubMed DOI
Delker A, Fendler WP, Kratochwil C, et al. Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2016;43:42–51. PubMed DOI
Baum RP, Kulkarni HR, Schuchardt C, et al. 177Lu-Labeled prostate-specific membrane Antigen Radioligand Therapy of Metastatic Castration-resistant prostate Cancer: Safety and Efficacy. J Nucl Med. 2016;57:1006–13. PubMed DOI
Roll W, Brauer A, Weckesser M, Bogemann M, Rahbar K. Long-term survival and excellent response to repeated 177Lu-Prostate-specific membrane Antigen 617 Radioligand Therapy in a patient with Advanced Metastatic Castration-resistant prostate Cancer. Clin Nucl Med. 2018.
Gallyamov M, Meyrick D, Barley J, Lenzo N. Renal outcomes of radioligand therapy: experience of 177lutetium-prostate-specific membrane antigen ligand therapy in metastatic castrate-resistant prostate cancer. Clin Kidney J. 2019;13:1049–55. PubMed DOI PMC
Kulkarni H, Schuchardt C, SINGH A, Langbein T, Baum R. Early initiation of Lu-177 PSMA radioligand therapy prolongs overall survival in metastatic prostate cancer. J Nucl Med. 2018;59:529.
Majer P, Jancarik A, Krecmerova M, et al. Discovery of orally available prodrugs of the glutamate carboxypeptidase II (GCPII) inhibitor 2-Phosphonomethylpentanedioic acid (2-PMPA). J Med Chem. 2016;59:2810–9. PubMed DOI
Chen Y, Pullambhatla M, Foss CA, et al. 2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pen tanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin Cancer Res. 2011;17:7645–53. PubMed DOI PMC
Rowe SP, Macura KJ, Mena E, et al. PSMA-Based [(18)F]DCFPyL PET/CT is Superior to Conventional Imaging for Lesion Detection in patients with metastatic prostate Cancer. Mol Imaging Biol. 2016;18:411–9. PubMed DOI PMC
Amor-Coarasa A, Kelly JM, Gruca M, et al. Continuation of comprehensive quality control of the itG 68Ge/68Ga generator and production of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for clinical research studies. Nucl Med Biol. 2017;53:37–9. PubMed DOI
Thorek DL, Watson PA, Lee SG, et al. Internalization of secreted antigen-targeted antibodies by the neonatal fc receptor for precision imaging of the androgen receptor axis. Sci Transl Med. 2016;8:367ra167. PubMed DOI PMC
Nedelcovych M, Dash RP, Tenora L, et al. Enhanced brain delivery of 2-(Phosphonomethyl)pentanedioic acid following Intranasal Administration of its gamma-substituted Ester Prodrugs. Mol Pharm. 2017;14:3248–57. PubMed DOI PMC
Fendler WP, Reinhardt S, Ilhan H, et al. Preliminary experience with dosimetry, response and patient reported outcome after 177Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer. Oncotarget. 2017;8:3581–90. PubMed DOI
Hohberg M, Eschner W, Schmidt M, et al. Lacrimal glands may represent organs at Risk for Radionuclide Therapy of prostate Cancer with [(177)Lu]DKFZ-PSMA-617. Mol Imaging Biol. 2016;18:437–45. PubMed DOI
Kabasakal L, Toklu T, Yeyin N, et al. Lu-177-PSMA-617 prostate-specific membrane Antigen inhibitor therapy in patients with castration-resistant prostate Cancer: Stability, Bio-distribution and Dosimetry. Mol Imaging Radionucl Ther. 2017;26:62–8. PubMed DOI PMC
Scarpa L, Buxbaum S, Kendler D, et al. The (68)Ga/(177)Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUVmax values and absorbed dose estimates. Eur J Nucl Med Mol Imaging. 2017;44:788–800. PubMed DOI
Yadav MP, Ballal S, Tripathi M, et al. Post-therapeutic dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-resistant prostate cancer. Nucl Med Commun. 2017;38:91–8. PubMed DOI
Bodei L, Cremonesi M, Ferrari M, et al. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging. 2008;35:1847–56. PubMed DOI
Kopka K, Benesova M, Barinka C, Haberkorn U, Babich J. Glu-ureido-based inhibitors of prostate-specific membrane Antigen: lessons learned during the development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers. J Nucl Med. 2017;58:s17–26. DOI
Kelly JM, Amor-Coarasa A, Nikolopoulou A, et al. Dual-target binding ligands with modulated pharmacokinetics for endoradiotherapy of prostate Cancer. J Nucl Med. 2017;58:1442–49. PubMed DOI
Kelly JM, Amor-Coarasa A, Ponnala S, et al. Trifunctional PSMA-Targeting constructs for prostate Cancer with unprecedented localization to LNCaP tumors. Eur J Nucl Med Mol Imaging. 2018;45:1841–51. PubMed DOI
Zang J, Fan X, Wang H et al. First-in-human study of (177)Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2018.
Schmidt A, Wirtz M, Farber SF, et al. Effect of Carbohydration on the Theranostic Tracer PSMA I&T. ACS Omega. 2018;3:8278–87. PubMed DOI PMC
Zang J, Liu Q, Sui H, et al. 177Lu-EB-PSMA Radioligand Therapy with escalating doses in patients with metastatic castration-resistant prostate Cancer. J Nucl Med. 2020;61:1772–8. PubMed DOI PMC
Kramer V, Fernandez R, Lehnert W, et al. Biodistribution and dosimetry of a single dose of albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC. Eur J Nucl Med Mol Imaging. 2021;48:893–903. PubMed DOI
Matteucci F, Mezzenga E, Caroli P, et al. Reduction of (68)Ga-PSMA renal uptake with mannitol infusion: preliminary results. Eur J Nucl Med Mol Imaging. 2017;44:2189–94. PubMed DOI
van Kalmthout LWM, Lam M, de Keizer B, et al. Impact of external cooling with icepacks on (68)Ga-PSMA uptake in salivary glands. EJNMMI Res. 2018;8:56. PubMed DOI PMC
Baum RP, Langbein T, Singh A, et al. Injection of Botulinum Toxin for preventing salivary gland toxicity after PSMA Radioligand Therapy: an empirical proof of a Promising Concept. Nucl Med Mol Imaging. 2018;52:80–1. PubMed DOI PMC
Kristiansson A, Timmermand OV, Altai M, et al. Hematological and renal toxicity in mice after three cycles of high activity [177Lu]Lu-PSMA-617 with or without human α1-microglobulin. Sci Rep. 2024;14(1):10787. PubMed DOI PMC
Kristiansson A, Orbom A, Ahlstedt J, et al. 177Lu-PSMA-617 therapy in mice, with or without the antioxidant α1-Microglobulin (A1M), including kidney damage Assessment using 99mTc-MAG3 imaging. Biomol. 2021;11(2):263.
Valkema R, Pauwels SA, Kvols LK, et al. Long-term follow-up of renal function after peptide receptor radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0), Tyr(3)-octreotate. J Nucl Med. 2005;46:s83–91.
Haberkorn U, Giesel F, Morgenstern A, Kratochwil C. The future of Radioligand Therapy: alpha, beta, or both? J Nucl Med. 2017;58:1017–8. PubMed DOI
Kratochwil C, Bruchertseifer F, Rathke H, et al. Targeted alpha-therapy of metastatic castration-resistant prostate Cancer with (225)Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding. J Nucl Med. 2017;58:1624–31. PubMed DOI
Gaertner FC, Halabi K, Ahmadzadehfar H, et al. Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. Oncotarget. 2017;8:55094–103. PubMed DOI PMC
Hauge A, Rofstad EK. Antifibrotic therapy to normalize the tumor microenvironment. J Transl Med. 2020;18:207. PubMed DOI PMC
Shemi A, Khvalevsky EZ, Gabai RM, et al. Multistep, effective drug distribution within solid tumors. Oncotarget. 2015;6:39564–77. PubMed DOI PMC
Rousseau E, Lau J, Kuo HT, et al. Monosodium glutamate reduces 68Ga-PSMA-11 uptake in salivary glands and kidneys in a preclinical prostate cancer model. J Nucl Med. 2018;59:1865–8. PubMed DOI PMC
Harsini S, Saprunoff H, Alden T, et al. The effects of monosodium glutamate on PSMA radiotracer uptake in men with recurrent prostate cancer: a prospective, randomized, double-blind, placebo-controlled intraindividual imaging study. J Nucl Med. 2021;62:81–7. PubMed DOI
Gorges TM, Riethdorf S, Ahsen O, et al. Heterogeneous PSMA expression on circulating tumor cells - a potential basis for stratification and monitoring of PSMA-directed therapies in prostate cancer. Oncotarget. 2016;7(23):34930–41. PubMed DOI PMC
Piron S, Verhoeven J, De Coster E, et al. Impact of the molar activity and PSMA expression level on [18F]AlF-PSMA-11 uptake in prostate cancer. Sci Rep. 2021;11(1):22623. PubMed DOI PMC
Luckerath K, Wei L, Fendler WP, et al. Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer. EJNMMI Res. 2018;8(1):96. PubMed DOI PMC
Lucaroni L, Georgiev T, Prodi E, et al. Cross-reactivity to glutamate carboxypeptidase III causes undesired salivary gland and kidney uptake of PSMA-targeted small-molecule radionuclide therapeutics. Eur J Nucl Med Mol Imaging. 2023;50(3):957–61. PubMed DOI
Lee Z, Heston WD, Wang X, Basilion JP. GCP III is not the off-target for urea-based PSMA ligands. Eur J Nucl Med Mol Imaging. 2023;50(10):2944–96. PubMed DOI PMC