177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry

Ayman Abouzayed; Kamila Seitova; Fanny Lundmark; Vitalina Bodenko; Maryam Oroujeni; Vladimir Tolmachev; Ulrika Rosenström; Anna Orlova

doi:10.3389/fonc.2023.1221103

¹⁷⁷Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry

Front Oncol. 2023 Sep 27:13:1221103. doi: 10.3389/fonc.2023.1221103. eCollection 2023.

Authors

Ayman Abouzayed¹, Kamila Seitova^{2

3}, Fanny Lundmark¹, Vitalina Bodenko^{2

3}, Maryam Oroujeni^{4

5}, Vladimir Tolmachev^{3

4}, Ulrika Rosenström¹, Anna Orlova^{1

6}

Affiliations

¹ Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
² Scientific and Research Laboratory of Chemical and Pharmaceutical Research, Siberian State Medical University, Tomsk, Russia.
³ Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk, Russia.
⁴ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
⁵ Affibody AB, Solna, Sweden.
⁶ Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Abstract

Introduction: Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that ¹⁷⁷Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy.

Methods: BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [¹⁷⁷Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo, target specificity and dosimetry. [¹⁷⁷Lu]Lu-PSMA-617 was simultaneously evaluated for comparison.

Results: BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [¹⁷⁷Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities K_D1 = 3.8 nM and K_D2 = 25 nM. The half-maximal inhibitory concentration for ^natLu-BQ7876 was 59 nM that is equal to 61 nM for ^natLu-PSMA-617. Cellular processing of [¹⁷⁷Lu]Lu-BQ7876 was accompanied by slow internalization. [¹⁷⁷Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3%ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen.

Discussion: Biodistribution studies in mice demonstrated that targeting properties of [¹⁷⁷Lu]Lu-BQ7876 are not inferior to properties of [¹⁷⁷Lu]Lu-PSMA-617, but do not offer any decisive advantages.

Keywords: PC3-pip cells; PSMA; dosimetry; lutetium-177; prostate cancer.

Grants and funding

This research was funded by the Swedish Cancer Society (Cancerfonden) (grant numbers 20-0815 PjF and 20 0814 UsF), the Swedish Research Council (Vetenskapsrådet) (grant numbers 2019-00986 and 2022-00556), and Grant of Ministry of Science and Higher Education of the Russian Federation (grant number 075-15-2022-1103).