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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

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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).

URL of registry

https://classic.clinicaltrials.gov/ct2/show/NCT05603559.

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Acknowledgements

Authors thank Drs. David Mankoff, Daniel Pryma (University of Pennsylvania) and Dr. William Eckelman (Five Eleven Pharma Inc.) for their valuable suggestions to this project. In loving memory of Tongyuan Cui (1995.8.5–2023.8.20) from Department of Engineering Physics, Tsinghua University, who encouraged and guided me (Linlin Li) towards making my career choice in radiopharmaceutical and nuclear medicine research.

Funding

This study was supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-C-004), the Fundamental Research Funds for the Central Universities (3332022110), Chinese Academy of Medical Science Innovation Fund for Medical Sciences (2021-I2M-1-016, 2022-I2M-C&T-A-008, 2022-I2M-2-002) and the National Natural Science Foundation of China (82272046, 22176016).

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Author notes

  1. Linlin Li, Jiarou Wang, Guochang Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing St., Dongcheng District, Beijing, 100730, China

    Linlin Li, Jiarou Wang, Rongxi Wang, Huimin Sui, Chenhao Jia, Yuanyuan Jiang & Zhaohui Zhu

  2. Department of Nuclear Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China

    Guochang Wang & Jie Zang

  3. College of Chemistry, Key Laboratory of Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing, 100875, China

    Wenbin Jin, Haiyan Hong & Lin Zhu

  4. Five Eleven Pharma Inc, Philadelphia, PA, 19104, USA

    David Alexoff, Karl Ploessl & Hank F. Kung

  5. Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, PA, 19104, USA

    Hank F. Kung

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  1. Linlin Li
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Corresponding authors

Correspondence to Hank F. Kung or Zhaohui Zhu.

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Ethics approval

This study was approved by the Institute Review Board of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (no. ZS-3567), and registered at clinicaltrials.gov (NCT05603559).

Conflict of interest

David Alexoff, Karl Ploessl and Hank F. Kung are employees of Five Eleven Pharma Inc. which holds the patent rights for [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088 and related technology. Dr. Hank F. Kung is also the Founder and Chairman of the board at Five Eleven Pharma Inc. Other authors declare no other conflict of interests.

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Li, L., Wang, J., Wang, G. et al. 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. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06721-x

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