Biomaterial Database

Preclinical dosimetric studies of 177 Lu-scFvD2B and comparison with 177 Lu-PSMA-617 and 177 Lu-iPSMA endoradiotherapeutic agents. 2021

Laura Meléndez-Alafort, and Guillermina Ferro-Flores, and Clara Santos-Cuevas, and Blanca Ocampo-García, and Sofia Turato, and Giulio Fracasso, and Cristina Bolzati, and Antonio Rosato, and Laura De Nardo

Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35138, Padua, Italy.

OBJECTIVE 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 (NSO ). 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 NSO 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 (NT ). 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 with 177 Lu-LMW agents.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D004151	Dipeptides	Peptides composed of two amino acid units.	Dipeptide
D006573	Heterocyclic Compounds, 1-Ring	Organic compounds that contain a ring structure made up of carbon and one or more additional elements such as nitrogen and oxygen.	Heterocyclic Cpds, 1-Ring,1-Ring Heterocyclic Compounds,1-Ring Heterocyclic Cpds,Heterocyclic Compounds, 1 Ring,Heterocyclic Cpds, 1 Ring
D000090324	Tumor Protein, Translationally-Controlled 1	A highly expressed protein in tumor cells, encoded by Tpt1 gene. It's involved in various cellular activities including protein synthesis, calcium-binding, MICROTUBULE stabilization, growth, and cell survival. Also, Tpt1 identified as a direct target gene of P53 tumor suppression.	Histamine Releasing Factor,Histamine Releasing Factor, Lymphocyte-Dependent,Histamine-Releasing Factor (IgE-Dependent),Protein P23, Ehrlich Ascites Tumor,TPT1 Protein,Translationally-Controlled Tumor Protein,Factor, Histamine Releasing,Histamine Releasing Factor, Lymphocyte Dependent,Protein, TPT1,Protein, Translationally-Controlled Tumor,Translationally Controlled Tumor Protein,Tumor Protein, Translationally Controlled 1,Tumor Protein, Translationally-Controlled
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000954	Antigens, Surface	Antigens on surfaces of cells, including infectious or foreign cells or viruses. They are usually protein-containing groups on cell membranes or walls and may be isolated.	Cell Surface Antigens,Surface Antigens,Surface Markers, Immunological,Cell Surface Antigen,Immunologic Surface Markers,Markers, Immunological Surface,Surface Antigen,Surface Markers, Immunologic,Antigen, Cell Surface,Antigen, Surface,Antigens, Cell Surface,Immunological Surface Markers,Markers, Immunologic Surface,Surface Antigen, Cell,Surface Antigens, Cell
D014018	Tissue Distribution	Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios.	Distribution, Tissue,Distributions, Tissue,Tissue Distributions
D017430	Prostate-Specific Antigen	A glycoprotein that is a kallikrein-like serine proteinase and an esterase, produced by epithelial cells of both normal and malignant prostate tissue. It is an important marker for the diagnosis of prostate cancer.	Kallikrein hK3,gamma-Seminoprotein,hK3 Kallikrein,Prostate Specific Antigen,Semenogelase,Seminin,Kallikrein, hK3,gamma Seminoprotein
D043425	Glutamate Carboxypeptidase II	A metallocarboxypeptidase that is predominantly expressed as a membrane-bound enzyme. It catalyzes the hydrolysis of an unsubstituted, C-terminal glutamyl residue, typically from PTEROYLPOLYGLUTAMIC ACIDS. It was formerly classified as EC 3.4.19.8.	FOLH1 Protein,Folate Hydrolase I,N-Acetylaspartylglutamate Peptidase,N-Acetylated-alpha-Linked Acidic Dipeptidase,NAAG Peptidase,NAALADase,NAALADase II,NAALADase L,Acidic Dipeptidase, N-Acetylated-alpha-Linked,Carboxypeptidase II, Glutamate,Dipeptidase, N-Acetylated-alpha-Linked Acidic,Hydrolase I, Folate,N Acetylaspartylglutamate Peptidase,N Acetylated alpha Linked Acidic Dipeptidase,Peptidase, N-Acetylaspartylglutamate
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus