Therapeutic efficacy of the radiopharmaceutical [Lu-177]Lu-PSMA I&T. Preclinical study

«Radiation and Risk», 2024, vol. 33, No. 2, pp.44-56

DOI: 10.21870/0131-3878-2024-33-2-44-56

Authors

Klementyeva O.E. – Lead. Researcher, C.Sc., Biol. N.N. Blokhin NMRCO. Contacts: 23 Kashirskoe shosse, Moscow, Russia, 115478. Tel.: +7 (985) 136-01-76; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .
Lunev A.S. – Head of Lab., C.Sc., Biol.
Petrosova K.A. – Researcher
Larenkov A.A. – Head of Dep., C.Sc., Chem. SRC – FMBC.
¹ N.N. Blokhin National Medical Research Center of Oncology, Moscow
² State Research Center – Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow

Abstract

The appearance of radiopharmaceuticals based on prostate-specific membrane antigen (PSMA) ligands labeled with beta- or alpha-emitting radionuclides led to a breakthrough on the development of targeted therapy for metastatic castration-resistant prostate cancer. For the completeness of the preclinical evaluation of therapeutic radiopharmaceuticals based on PSMA, the study of their effectiveness should be supplemented by an assessment of absorbed doses of internal radiation in ex-perimental tumor foci. The objectives of this study were: 1) Examine the dose-effect relationship to assess the therapeutic efficacy of [177Lu]Lu-PSMA I&T with activities comparable to those of humans; 2) Assessing the expected absorbed dose levels created in 22RV1 xenografts after the therapeutic effects have been introduced, with the potential for both minimal and maximum radiopharma-ceutical accumulation. The studies were conducted on male nu/nu mice with subcutaneous 22RV1 xenografts. The dynamic of accumulation was examined after 2.2 MBq of a radiopharmaceutical was introduced. The main findings were obtained when [177Lu]Lu-PSMA was introduced at 9.2 MBq (EDmin) and 36.6 MBq (EDmax). A statistically significant dose-dependent inhibition of xenograft growth was found compared with the control. The expected absorbed doses for EDmin in xenografts were between 2.7 Gy for minimal accumulation and 3.9 Gy for maximum accumulation. For EDmax in a similar scenario, this range was 10.7 to 15.5 Gy. The results support the preclinical assessment's informationality in determining the range of doses absorbed in tumor foci that cause the observed therapeutic effects.

Key words
radiopharmaceutical, ¹⁷⁷Lu, prostate-specific membrane antigen, prostate cancer, radionuclide therapy, preclinical studies, therapeutic effects, absorbed doses, oncology, radiation therapy, nuclear medicine.

References

1. Ferlay J., Colombet M., Soerjomataram I., Parkin D.M., Piñeros M., Znaor A., Bray F. Cancer statistics for the year 2020: an overview. Int. J. Cancer, 2021, vol. 149, no. 4, pp. 778-789.

2. Salikhar R.I., Tumanbayev A.M., Kerimov A.D., Kamarli Z.P., Makimbetov E.K. Epidemiology of prostate cancer. Nauchnoye obozreniye. Meditsinskiye nauki – Scientific Review. Medical Sciences, 2020, no. 3, pp. 15-20. (In Russian).

3. Hennrich U., Eder M. [177Lu]Lu-PSMA-617 (PluvictoTM): the first FDA-approved radiotherapeutical for treat-ment of prostate cancer. Pharmaceuticals (Basel), 2022, vol. 15, no. 10, pp. 1292. DOI: 10.3390/ph15101292.

4. Weineisen M., Schottelius M., Simecek J., Baum R.P., Yildiz A., Beykan S., Kulkarni H.R., Lassmann M., Klette I., Eiber M., Schwaiger M., Wester H.J. 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, vol. 56, no. 8, pp. 1169-1176.

5. Vlasova O.P., German K.E., Krilov V.V., Petriev V.M., Epstein N.B. New radiopharmaceuticals based on prostate-specific inhibitors of membrane antigen for diagnostics and therapy of metastatic prostate cancer. Vestnik Rossiyskoy akademii meditsinskikh nauk – Annals of the Russian Academy of medical sciences, 2015, vol. 70, no. 3, pp. 360-365. (In Russian).

6. Tateishi U. Prostate-specific membrane antigen (PSMA)-ligand positron emission tomography and radioligand therapy (RLT) of prostate cancer. Jpn. J. Clin. Oncol., 2020, vol. 50, no. 4, pp. 349-356.

7. Medvedeva A.A., Chernov V.I., Usinin E.A., Zelchan R.V., Bragina O.D., Lushnikova N.A. Use of 177Lu-PSMA for radionuclide therapy in patients with castrate-resistant prostate cancer. Sibirskiy onkologicheskiy zhurnal – Siberian Journal of Oncology, 2021, vol. 20, no. 3, pp. 115-123. (In Russian).

8. 177Lu-PSMA-I&T PSMA Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer. Phase 2 clinical trial. ClinicalTrials.gov Identifier: NCT04188587: database. Available at: https://classic.clinicaltri-als.gov/ct2/show/NCT04188587?term=NCT04188587&draw=2&rank=1 (Accessed 06.06.2022).

9. Guidelines for preclinical drug research. Part One. Ed.: A.N. Mironov. Moscow, Grif and K Publ., 2012. 244 p. (In Russian).

10. Rosar F., Schön N., Bohnenberger H., Bartholomä M., Stemler T., Maus S., Khreish F., Ezziddin S., Schaefer-Schuler A. Comparison of different methods for post-therapeutic dosimetry in [177Lu]Lu-PSMA-617 radioligand therapy. EJNMMI Phys., 2021, vol. 8, no. 1, pp. 40. DOI: 10.1186/s40658-021-00385-4.

11. Goorley T., James M., BoothT., Brown F., Bull J., Cox L.J., Durkee J., Elson J., Fensin M., Forster R.A., Hendricks J., Hughes H.G., Johns R., Kiedrowski B., Martz R., Mashnik S., McKinney G., Pelowitz D., Prael R., Sweezy J., Waters L., Wilcox T., Zukaitis T. Initial MCNP6 release overview. Nucl. Technol., 2012, vol. 180, no. 3, pp. 298-315.

12. Tomayko M.M., Reynolds C.P. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother. Pharmacol., 1989, vol. 24, no. 3, pp. 148-154.

13. Treshchalina E.M., Zhukova O.S., Gerasimova G.K., Andronova N.V., Garin A.M. Guidelines for the study of antitumor activity of pharmacological substances. Guidelines for the experimental (preclinical) study of new phar-macological substances. Ed.: R.U. Khabriyev, 2nd ed. Moscow, Meditsina Publ., 2005, рр. 637-651. (In Russian).

14. Smirnova Z.S., Gerasimova G.K., Andronova N.V., Garin A.M., Sokolova A.S. Guidelines for the study of specific pharmacological activity proposed for the treatment of hormone-dependent tumors. Guidelines for the experimental (preclinical) study of new pharmacological substances. Ed.: R.U. Khabriyev, 2nd ed. Moscow, Meditsina Publ., 2005, рр. 653-668. (In Russian).

15. Close B., Banister K., Baumans V., Bernoth E.M., Bromage N., Bunyan J., Bunyan J., Erhardt W., Flecknell P., Gregory N., Hackbarth H., Morton D., Warwick C. Recommendations for euthanasia of ex-perimental animals: Part 1. DGXI of the European Commission. Lab. Anim., 1996, vol. 30, no. 4, pp. 293-316.

16. Close B., Banister K., Baumans V., Bernoth E.M., Bromage N., Bunyan J., Erhardt W., Flecknell P., Gregory N., Hackbarth H., Morton D., Warwick C. Recommendations for euthanasia of experimental ani-mals: Part 2. DGXT of the European Commission. Lab. Anim., 1997, vol. 31, no. 1, рр. 1-32.

17. Guide for the care and use of laboratory animals. Eighth Edition. Washington, DC: The National Academies Press., 2011. 246 p.

18. The guide to laboratory animals and alternative models in biomedical technologies. Eds.: N.N. Karkishchenko, S.V. Grachev. Moscow, Profil’-2С Publ., 2010. 344 p. (In Russian).

19. Yusufi N., Wurzer A., Herz M., D'Alessandria C., Feuerecker B., Weber W., Wester H.J., Nekolla S., Eiber M. Comparative preclinical biodistribution, dosimetry, and endoradiotherapy in metastatic castration-resistant pros-tate cancer using 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMAI&T. J. Nucl. Med., 2021, vol. 62, no. 8, pp. 1106-1111.

20. Resch S., Takayama Fouladgar S., Zacherl M., Sheikh G.T., Liubchenko G., Rumiantcev M., Unterrainer L.M., Wenter V., Bartenstein P., Ziegler S.I., Ilhan H., Beyer L., Böning G., Delker A. Investigation of image-based lesion and kidney dosimetry protocols for 177Lu-PSMA-I&T therapy with and without a late SPECT/CT acquisition. EJNMMI Physics, 2023, vol. 10, no. 1, pp. 11. DOI: 10.1186/s40658-023-00529-8.

21. Okamoto S., Thieme A., Allmann J., D'Alessandria C., Maurer T., Retz M., Tauber R., Heck M.M., Wester H.J., Tamaki N., Fendler W.P., Herrmann K., Pfob C.H., Scheidhauer K., Schwaiger M., Ziegler S., Eiber M. Radiation dosimetry for 177Lu-PSMA I&T in metastatic castration-resistant prostate cancer: absorbed dose in normal organs and tumor lesions. J. Nucl. Med., 2017, vol. 58, no. 3, pp. 445-450.

Full-text article (in Russian)