Preclinical dosimetric studies of ¹⁷⁷Lu‐scFvD2B and comparison with ¹⁷⁷Lu‐PSMA‐617 and ¹⁷⁷Lu‐iPSMA endoradiotherapeutic agents

Abstract

Internal dosimetry has become a very important tool to evaluate the risks and benefits of new endoradiotherapeutic agents. Nowadays, some of the most successful targeted radionuclide therapy (TRT) agents are 177 Lu-DOTA conjugates based on low molecular weight (LMW) Glu-ureido PSMA inhibitors. It has, however, been demonstrated that the DOTA chelating moiety reduces the internalization of the LMW-PSMA agent and its radiation dose to the tumor. Previously, we reported that 177 Lu-scFvD2B, an antibody-based construct, demonstrated statistically significant higher cell uptake and internalization in LNCaP prostate cancer (PCa) cells (PSMA-positive) when compared to the LMW-PSMA agents, 177 Lu-PSMA-617 and 177 Lu-iPSMA, two of the endoradiotherapeutic agents which currently are the most used in PCa therapy. The aim of this study is to estimate the preclinical 177 Lu-scFvD2B organ and tumor-absorbed doses, and to compare the values with those of 177 Lu-PSMA-617 and 177 Lu-iPSMA. Methods: 177 Lu-scFvD2B, 177 Lu-PSMA-617, and 177 Lu-iPSMA were prepared and their radiochemical purity determined. Biodistribution studies of each radiopharmaceutical were then carried out in healthy mice to define the main source organs (SO) and to calculate the number of disintegrations in each source organs per unit of administered activity (N SO ). Absorbed dose in the main organs were then calculated for each 177 Lu-conjugate by means of OLINDA/EXM 2.1.1 software, using the calculated N SO for both the adult male and the mouse phantoms as program inputs. Images of mice bearing micropulmonary tumors injected with 177 Lu-conjugates were also obtained. Tumor standardized uptake values (SUV) for the different conjugates, obtained from the 3D SPECT image reconstruction of these mice, were used as the number of disintegrations in a tumor site per unit of administered activity (N T ). The tumor-absorbed dose was calculated using the published electron dose S-values for sphere models with diameters ranging from 10 µm to 10 mm and considering a uniform activity distribution and tumor density equivalent to water density. Results: All 177 Lu-labeled agents were obtained in high yield (98%). Dosimetric studies carried out using mouse phantoms demonstrated that organ absorbed doses of 177 Lu-scFvD2B were from 1.4 to 2.3 times higher than those for 177 Lu-iPSMA and from 1.5 to 2.6 times higher than those for 177 Lu-PSMA-617. However, the 177 Lu-scFvD2B values of tumor-absorbed doses for all investigated tumor sizes were from 2.8 to 3.0 times greater than those calculated for 177 Lu-iPSMA and 177 Lu-PSMA-617, respectively. Moreover, 177 Lu-scFvD2B showed the highest tumor/kidney ratio when compared to those reported for 177 Lu-albumin conjugates. Conclusions: In this preclinical study, we demonstrated the potential of 177 Lu-scFvD2B as a therapeutic agent for PSMA-expressing tumors, due to its higher tumor-absorbed dose when compared 4064

Development and Characterization of 99mTc-scFvD2B as a Potential Radiopharmaceutical for SPECT Imaging of Prostate Cancer

“…This study evaluated the feasibility of using technetium-labeled scFvD2B as a theranostic pair for 177 Lu-labeled scFvD2B. 177 Lu-scFvD2B is currently under preclinical investigation because it has shown increased prostate cancer cell uptake, internalization and tumor radiation dose as compared to the Glu-ureido-based PSMA inhibitor peptides labeled with 177 Lu [ 31 , 33 ]. Different types of chelators can be used for scFvD2B because, unlike PSMA inhibitor peptides, the pharmacokinetic properties (including cellular internalization and biodistribution of scFvD2B), have been shown not to be significantly affected by the chelator [ 31 , 32 ].…”

“…Different types of chelators can be used for scFvD2B because, unlike PSMA inhibitor peptides, the pharmacokinetic properties (including cellular internalization and biodistribution of scFvD2B), have been shown not to be significantly affected by the chelator [ 31 , 32 ]. The decision to label the scFvD2B with 99m Tc was based on the fact that it has a slower tumor uptake (3 h) than PSMA peptides [ 33 ] and is therefore not a good candidate for labeling with a very short half-life radionuclide such as 68 Ga. Moreover, despite the higher spatial resolution and sensitivity of 68 Ga-PSMA agents, some recently developed 99m Tc-PSMAs have proven to be a cost-effective alternative to 68 Ga tracers due to the lower cost and greater availability of 99m Tc, as well as the presence of SPECT in most hospitals worldwide [ 18 ].…”

“…Different types of chelators can be used for scFvD2B because, unlike PSMA inhibitor peptides, the pharmacokinetic properties (including cellular internalization and biodistribution of scFvD2B), have been shown not to be significantly affected by the chelator [31,32]. The decision to label the scFvD2B with 99m Tc was based on the fact that it has a slower tumor uptake (3 h) than PSMA peptides [33] and is therefore…”

“…It has been reported that small antibody fragments can access binding sites more uniformly and penetrate solid tumors more homogeneously and efficiently than full-length antibodies [ 30 ]. In vivo imaging of scFvD2B radiolabeled with different radionuclides ( 123 I, 111 In and 177 Lu) confirmed the relatively fast and high antigen-positive tumor uptake (from 3 h post-injection), with a short circulatory half-life and rapid clearance from most of the non-target tissues, allowing labeling with radionuclides of relatively short physical half-life (t 1/2 ) such as 99m Tc (t 1/2 = 6 h) [ 31 , 32 , 33 ]. Moreover, due to its larger size compared to PSMA-derived peptides, scFvD2B can be conjugated to different chelating agents without drastically affecting its binding affinity and pharmacokinetic properties [ 29 , 32 ].…”