Skip to main content
Top

25-04-2024 | Prostate Cancer | Original Article

Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study

Authors: Linlin Li, Jiarou Wang, Guochang Wang, Rongxi Wang, Wenbin Jin, Jie Zang, Huimin Sui, Chenhao Jia, Yuanyuan Jiang, Haiyan Hong, Lin Zhu, David Alexoff, Karl Ploessl, Hank F. Kung, Zhaohui Zhu

Published in: European Journal of Nuclear Medicine and Molecular Imaging

Login to get access

Abstract

Purpose

Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [177Lu]Lu-P17-087, and its albumin binder modified derivative, [177Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3).

Methods

Patients with PSMA-positive tumors were enrolled after [68Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [177Lu]Lu-P17-087 and four other patients received [177Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168 h after injection and one SPECT/CT imaging was performed at 24 h post-injection for each patient. Dosimetry evaluation was compared in both patient groups.

Results

Patients showed no major clinical side-effects under this low dose treatment. As expected [177Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [177Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [177Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [177Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively.

Conclusion

[177Lu]Lu-P17-088 and [177Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy.

Trial registration

177Lu-P17-087/177Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022).
Appendix
Available only for authorised users
Literature
3.
go back to reference Jang A, Kendi AT, Sartor O. Status of PSMA-targeted radioligand therapy in prostate cancer: current data and future trials. Ther Adv Med Oncol. 2023;15:1–12.CrossRef Jang A, Kendi AT, Sartor O. Status of PSMA-targeted radioligand therapy in prostate cancer: current data and future trials. Ther Adv Med Oncol. 2023;15:1–12.CrossRef
5.
go back to reference Hennrich U, Eder M. [177Lu]Lu-PSMA-617 (PluvictoTM): the first FDA-Approved Radiotherapeutical for treatment of prostate Cancer. Pharmaceuticals. 2022;15:1292.CrossRefPubMedPubMedCentral Hennrich U, Eder M. [177Lu]Lu-PSMA-617 (PluvictoTM): the first FDA-Approved Radiotherapeutical for treatment of prostate Cancer. Pharmaceuticals. 2022;15:1292.CrossRefPubMedPubMedCentral
6.
go back to reference Kratochwil C, Fendler WP, Eiber M, Hofman MS, Emmett L, Calais J et al. Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT). Eur J Nucl Med Mol Imaging. 2023:1–16. Kratochwil C, Fendler WP, Eiber M, Hofman MS, Emmett L, Calais J et al. Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT). Eur J Nucl Med Mol Imaging. 2023:1–16.
19.
23.
go back to reference Schuchardt C, Zhang J, Kulkarni HR, Chen X, Müller D, Baum RP. Prostate-specific membrane antigen radioligand therapy using 177Lu-PSMA I&T and 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer: comparison of safety, biodistribution, and dosimetry. J Nucl Med. 2022;63:1199–207.CrossRefPubMedPubMedCentral Schuchardt C, Zhang J, Kulkarni HR, Chen X, Müller D, Baum RP. Prostate-specific membrane antigen radioligand therapy using 177Lu-PSMA I&T and 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer: comparison of safety, biodistribution, and dosimetry. J Nucl Med. 2022;63:1199–207.CrossRefPubMedPubMedCentral
30.
go back to reference Lee H, Scheuermann JS, Young AJ, Doot RK, Daube-Witherspoon ME, Schubert EK, et al. Preliminary evaluation of 68Ga-P16-093, a PET Radiotracer Targeting prostate-specific membrane Antigen in prostate Cancer. Mol Imaging Biol. 2022;26:1–11. Lee H, Scheuermann JS, Young AJ, Doot RK, Daube-Witherspoon ME, Schubert EK, et al. Preliminary evaluation of 68Ga-P16-093, a PET Radiotracer Targeting prostate-specific membrane Antigen in prostate Cancer. Mol Imaging Biol. 2022;26:1–11.
32.
go back to reference Dumelin CE, Scheuermann J, Melkko S, Neri D. Selection of streptavidin binders from a DNA-encoded chemical library. Bioconjug Chem. 2006;17:366–70.CrossRefPubMed Dumelin CE, Scheuermann J, Melkko S, Neri D. Selection of streptavidin binders from a DNA-encoded chemical library. Bioconjug Chem. 2006;17:366–70.CrossRefPubMed
40.
go back to reference Ha S, Park C, Boo SH, Yoo IR, Moon HW, Chi DY, et al. Dosimetric Analysis of a phase I study of PSMA-Targeting Radiopharmaceutical Therapy with [177Lu]ludotadipep in patients with metastatic castration-resistant prostate Cancer. Korean J Radiol. 2024;25:179–88.CrossRefPubMedPubMedCentral Ha S, Park C, Boo SH, Yoo IR, Moon HW, Chi DY, et al. Dosimetric Analysis of a phase I study of PSMA-Targeting Radiopharmaceutical Therapy with [177Lu]ludotadipep in patients with metastatic castration-resistant prostate Cancer. Korean J Radiol. 2024;25:179–88.CrossRefPubMedPubMedCentral
41.
go back to reference Kramer V, Fernández R, Lehnert W, Jiménez-Franco LD, Soza-Ried C, Eppard E, 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.CrossRefPubMed Kramer V, Fernández R, Lehnert W, Jiménez-Franco LD, Soza-Ried C, Eppard E, 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.CrossRefPubMed
42.
go back to reference Borgna F, Deberle LM, Cohrs S, Schibli R, Müller C. Combined application of albumin-binding [177Lu]Lu-PSMA-ALB-56 and fast-cleared psma inhibitors: optimization of the Pharmacokinetics. Mol Pharm. 2020;17:2044–53.CrossRefPubMed Borgna F, Deberle LM, Cohrs S, Schibli R, Müller C. Combined application of albumin-binding [177Lu]Lu-PSMA-ALB-56 and fast-cleared psma inhibitors: optimization of the Pharmacokinetics. Mol Pharm. 2020;17:2044–53.CrossRefPubMed
43.
go back to reference Derlin T, Riethdorf S, Schumacher U, Lafos M, Peine S, Coith C, et al. PSMA-heterogeneity in metastatic castration‐resistant prostate cancer: circulating tumor cells, metastatic tumor burden, and response to targeted radioligand therapy. Prostate. 2023;1–13. https://doi.org/10.1002/pros.24549. Derlin T, Riethdorf S, Schumacher U, Lafos M, Peine S, Coith C, et al. PSMA-heterogeneity in metastatic castration‐resistant prostate cancer: circulating tumor cells, metastatic tumor burden, and response to targeted radioligand therapy. Prostate. 2023;1–13. https://​doi.​org/​10.​1002/​pros.​24549.
Metadata
Title
Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study
Authors
Linlin Li
Jiarou Wang
Guochang Wang
Rongxi Wang
Wenbin Jin
Jie Zang
Huimin Sui
Chenhao Jia
Yuanyuan Jiang
Haiyan Hong
Lin Zhu
David Alexoff
Karl Ploessl
Hank F. Kung
Zhaohui Zhu
Publication date
25-04-2024
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-024-06721-x