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177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of 177Lu.

Methods

We synthesized 14 new PSMA-targeted, 177Lu-labeled radioligands (177Lu-L1–177Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(−) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177Lu-L1, 177Lu-L3, 177Lu-L5 and 177Lu-PSMA-617. Efficacy of 177Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice.

Results

Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177Lu-L1, 177Lu-L3 and 177Lu-L5 demonstrated comparable uptake to 177Lu-PSMA-617 and 177Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177Lu-L1, 177Lu-L3 and 177Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177Lu-L1, most likely related to the fast renal clearance of this agent.

Conclusions

177Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.

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Abbreviations

PC:

Prostate cancer

SAR:

Structure–activity relationships

PSMA:

Prostate-specific membrane antigen

DCIBzL:

2-[3-[1-Carboxy-5-(4-(125)I-iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid

PET:

Positron emission tomography

SPECT:

Single-photon emission computed tomography.

References

  1. Kiess AP, Banerjee SR, Mease RC, Rowe SP, Rao A, Foss CA, et al. Prostate-specific membrane antigen as a target for cancer imaging and therapy. Quarterly J Nucl Med Mol Imaging. 2015;59:241–68.

    CAS  Google Scholar 

  2. Haberkorn U, Eder M, Kopka K, Babich JW, Eisenhut M. New strategies in prostate cancer: prostate-specific membrane antigen (PSMA) ligands for diagnosis and therapy. Clin Cancer Res. 2016;22:9–15.

    Article  CAS  Google Scholar 

  3. Osborne JR, Akhtar NH, Vallabhajosula S, Anand A, Deh K, Tagawa ST. Prostate-specific membrane antigen-based imaging. Urol Oncol. 2013;31:144–54.

    Article  CAS  Google Scholar 

  4. Salas Fragomeni RA, Amir T, Sheikhbahaei S, Harvey SC, Javadi MS, Solnes LB, et al. Imaging of nonprostate cancers using PSMA-targeted radiotracers: rationale, current state of the field, and a call to arms. J Nucl Med. 2018;59:871–7.

    Article  Google Scholar 

  5. Chang SS, O’Keefe DS, Bacich DJ, Reuter VE, Heston WD, Gaudin PB. Prostate-specific membrane antigen is produced in tumor-associated neovasculature. Clin Cancer Res. 1999;5:2674–81.

    CAS  PubMed  Google Scholar 

  6. Baccala A, Sercia L, Li J, Heston W, Zhou M. Expression of prostate-specific membrane antigen in tumor-associated neovasculature of renal neoplasms. Urology. 2007;70:385–90.

    Article  Google Scholar 

  7. Spatz S, Tolkach Y, Jung K, Stephan C, Busch J, Ralla B, et al. Comprehensive evaluation of prostate specific membrane antigen expression in the vasculature of renal tumors: implications for imaging studies and prognostic role. J Urol. 2018;199:370–7.

    Article  Google Scholar 

  8. 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.

    CAS  Google Scholar 

  9. Hrkach J, Von Hoff D, Ali MM, Andrianova E, Auer J, Campbell T, et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med. 2012;4:128ra39.

    Article  Google Scholar 

  10. Sterzing F, Kratochwil C, Fiedler H, Katayama S, Habl G, Kopka K, et al. 68Ga-PSMA-11 PET/CT: a new technique with high potential for the radiotherapeutic management of prostate cancer patients. Eur J Nucl Med Mol Imaging. 2016;43:34–41.

    Article  CAS  Google Scholar 

  11. Rowe SP, Macura KJ, Ciarallo A, Mena E, Blackford A, Nadal R, et al. Comparison of prostate-specific membrane antigen–based 18F-DCFBC PET/CT to conventional imaging modalities for detection of hormone-naïve and castration-resistant metastatic prostate cancer. J Nucl Med. 2016;57:46–53.

    Article  CAS  Google Scholar 

  12. Rahbar K, Afshar-Oromieh A, Seifert R, Wagner S, Schäfers M, Bögemann M, et al. Diagnostic performance of 18F-PSMA-1007 PET/CT in patients with biochemical recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2018;45:2055–61.

    Article  CAS  Google Scholar 

  13. Benesova M, Schafer M, Bauder-Wust U, Afshar-Oromieh A, Kratochwil C, Mier W, et al. Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med. 2015;56:914–20.

    Article  CAS  Google Scholar 

  14. Weineisen M, Schottelius M, Simecek J, Baum RP, Yildiz A, Beykan S, et al. 68Ga- and 177Lu-labeled PSMA I&T: optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies. J Nucl Med. 2015;56:1169–76.

    Article  CAS  Google Scholar 

  15. Fendler WP, Rahbar K, Herrmann K, Kratochwil C, Eiber M. 177Lu-PSMA radioligand therapy for prostate cancer. J Nucl Med. 2017;58:1196–200.

    Article  CAS  Google Scholar 

  16. Zechmann CM, Afshar-Oromieh A, Armor T, Stubbs JB, Mier W, Hadaschik B, et al. Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging. 2014;41:1280–92.

    Article  CAS  Google Scholar 

  17. Langbein T, Chausse G, Baum RP. Salivary gland toxicity of PSMA radioligand therapy: relevance and preventive strategies. J Nucl Med. 2018;59:1172–3.

    Article  CAS  Google Scholar 

  18. Kopka K, Benešová M, Bařinka 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;58:17S–26S.

    Article  CAS  Google Scholar 

  19. Trover JK, Beckett ML, Wright GL. Detection and characterization of the prostate-specific membrane antigen (PSMA) in tissue extracts and body fluids. Int J Cancer. 1995;62:552–8.

    Article  Google Scholar 

  20. Ray Banerjee S, Pullambhatla M, Foss CA, Falk A, Byun Y, Nimmagadda S, et al. Effect of chelators on the pharmacokinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA). J Med Chem. 2013;56:6108–21.

    Article  CAS  Google Scholar 

  21. Banerjee SR, Pullambhatla M, Foss CA, Nimmagadda S, Ferdani R, Anderson CJ, et al. 64Cu-labeled inhibitors of prostate-specific membrane antigen for PET imaging of prostate cancer. J Med Chem. 2014;57:2657–69.

    Article  CAS  Google Scholar 

  22. Eder M, Schaefer M, Bauder-Wuest U, Hull W-E, Waengler C, Mier W, et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012;23:688–97.

    Article  CAS  Google Scholar 

  23. Choy CJ, Ling X, Geruntho JJ, Beyer SK, Latoche JD, Langton-Webster B, et al. 177Lu-labeled phosphoramidate-based PSMA inhibitors: the effect of an albumin binder on biodistribution and therapeutic efficacy in prostate tumor-bearing mice. Theranostics. 2017;7:1928–39.

    Article  CAS  Google Scholar 

  24. Umbricht CA, Benesova M, Schibli R, Muller C. Preclinical development of novel PSMA-targeting radioligands: modulation of albumin-binding properties to improve prostate cancer therapy. Mol Pharm. 2018;15:2297–306.

    Article  CAS  Google Scholar 

  25. Kelly J, Amor-Coarasa A, Ponnala S, Nikolopoulou A, Williams C Jr, Schlyer D, et al. Trifunctional PSMA-targeting constructs for prostate cancer with unprecedented localization to LNCaP tumors. Eur J Nucl Med Mol Imaging. 2018.2018;45:1841–1851.

  26. Banerjee SR, Foss CA, Pullambhatla M, Wang Y, Srinivasan S, Hobbs RF, et al. Preclinical evaluation of 86Y-labeled inhibitors of prostate-specific membrane antigen for dosimetry estimates. J Nucl Med. 2015;56:628–34.

  27. Chen Y, Foss CA, Byun Y, Nimmagadda S, Pullambahatla M, Fox JJ, et al. Radiohalogenated prostate-specific membrane antigen (PSMA)-based ureas as imaging agents for prostate cancer. J Med Chem. 2008;51:7933–43.

    Article  CAS  Google Scholar 

  28. Kiess AP, Minn I, Vaidyanathan G, Hobbs RF, Josefsson A, Shen C, et al. (2S)-2-(3-(1-Carboxy-5-(4-211At-astatobenzamido)pentyl)ureido)-pentanedioic acid for PSMA-targeted alpha-particle radiopharmaceutical therapy. J Nucl Med. 2016;57:1569–75.

  29. Banerjee SR, Pullambhatla M, Byun Y, Nimmagadda S, Foss CA, Green G, et al. Sequential SPECT and optical imaging of experimental models of prostate cancer with a dual modality inhibitor of the prostate-specific membrane antigen. Angew Chem Int Ed. 2011;50:9167–70.

    Article  CAS  Google Scholar 

  30. Ray Banerjee S, Chen Z, Pullambhatla M, Lisok A, Chen J, Mease RC, et al. Preclinical comparative study of 68Ga-labeled DOTA, NOTA, and HBED-CC chelated radiotracers for targeting PSMA. Bioconjug Chem. 2016;27:1447–55.

    Article  CAS  Google Scholar 

  31. Kiess AP, Minn I, Chen Y, Hobbs R, Sgouros G, Mease RC, et al. Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen. J Nucl Med. 2015;56:1401–7.

    Article  CAS  Google Scholar 

  32. Chen Y, Chatterjee S, Lisok A, Minn I, Pullambhatla M, Wharram B, et al. A PSMA-targeted theranostic agent for photodynamic therapy. J Photochem Photobiol B Biol. 2017;167:111–6.

    Article  CAS  Google Scholar 

  33. Fendler WP, Stuparu AD, Evans-Axelsson S, Luckerath K, Wei L, Kim W, et al. Establishing 177Lu-PSMA-617 radioligand therapy in a syngeneic model of murine prostate cancer. J Nucl Med. 2017;58:1786–92.

    Article  CAS  Google Scholar 

  34. Bouchet LG, Bolch WE, Blanco HP, Wessels BW, Siegel JA, Rajon DA, et al. MIRD Pamphlet No. 19: absorbed fractions and radionuclide S values for six age-dependent multiregion models of the kidney. J Nucl Med. 2003;44:1113–47.

    PubMed  Google Scholar 

  35. Olszewski RT, Bukhari N, Zhou J, Kozikowski AP, Wroblewski JT, Shamimi-Noori S, et al. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J Neurochem. 2004;89:876–85.

    Article  CAS  Google Scholar 

  36. Brayton C. Chapter 25 - spontaneous diseases in commonly used mouse strains. In: Fox JG, Davisson MT, Quimby FW, Barthold SW, Newcomer CE, Smith AL, editors. The mouse in biomedical research. second ed. Burlington: Academic; 2007. p. 623–717.

    Chapter  Google Scholar 

  37. Brayton CF, Treuting PM, Ward JM. Pathobiology of aging mice and GEM: background strains and experimental design. Vet Pathol. 2012;49:85–105.

    Article  CAS  Google Scholar 

  38. Serfilippi LM, Pallman DR, Russell B. Serum clinical chemistry and hematology reference values in outbred stocks of albino mice from three commonly used vendors and two inbred strains of albino mice. Contemp Top Lab Anim Sci. 2003;42:46–52.

    CAS  PubMed  Google Scholar 

  39. Banerjee SR, Foss CA, Castanares M, Mease RC, Byun Y, Fox JJ, et al. Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA). J Med Chem. 2008;51:4504–17.

    Article  CAS  Google Scholar 

  40. Ray Banerjee S, Pullambhatla M, Foss CA, Falk A, Byun Y, Nimmagadda S, et al. Effect of chelators on the pharmacokinetics of 99mTc-labeled imaging agents for the prostate-specific membrane antigen (PSMA). J Med Chem. 2013;56:6108–21.

    Article  CAS  Google Scholar 

  41. Zang J, Fan X, Wang H, Liu Q, Wang J, Li H, et al. First-in-human study of 177Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46:148–58.

    Article  CAS  Google Scholar 

  42. Taïeb D, Foletti J-M, Bardiès M, Rocchi P, Hicks RJ, Haberkorn U. PSMA-targeted radionuclide therapy and salivary gland toxicity: why does it matter? J Nucl Med. 2018;59:747–8.

    Article  Google Scholar 

  43. Kratochwil C, Bruchertseifer F, Rathke H, Bronzel M, Apostolidis C, Weichert W, et al. Targeted alpha therapy of mCRPC with 225Actinium-PSMA-617: dosimetry estimate and empirical dose finding. J Nucl Med. 2017;58:1624–31.

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Acknowledgments

We would like to thank Dr. R. Mease for his helpful comments.

Funding

We are grateful for the following sources of support: K25 CA148901 and the Patrick C. Walsh Prostate Cancer Research Fund (SRB), CA134675, CA184228, EB024495, and the Commonwealth Foundation (MGP).

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Authors and Affiliations

  1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Sangeeta Ray Banerjee, Vivek Kumar, Ala Lisok, Jian Chen, Il Minn, Mary Brummet, Srikanth Boinapally, Michael Cole, Ethel Ngen, Bryan Wharram, Robert F. Hobbs & Martin G. Pomper

  2. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Sangeeta Ray Banerjee & Martin G. Pomper

  3. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Cory Brayton

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  1. Sangeeta Ray Banerjee
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Correspondence to Sangeeta Ray Banerjee or Martin G. Pomper.

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Conflict of interest

Drs. Banerjee and Pomper are co-inventors on one or more U.S. patents covering compounds discussed in this submission, and as such are entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. No other authors have declared any relevant conflicts of interest.

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All animal studies were carried out in compliance with the regulations of the Johns Hopkins Animal Care and Use Committee.

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Banerjee, S.R., Kumar, V., Lisok, A. et al. 177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy. Eur J Nucl Med Mol Imaging 46, 2545–2557 (2019). https://doi.org/10.1007/s00259-019-04434-0

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