Preclinical Dosimetry, Imaging, and Targeted Radionuclide Therapy Studies of Lu-177-Labeled Albumin-Binding, PSMA-Targeted CTT1403

Ling, Xiaoxi; Latoche, Joseph D.; Choy, Cindy J.; Kurland, Brenda F.; Laymon, Charles M.; Wu, Yijen; Salamacha, Nathan; Ding, Shan; Geruntho, Jonathan J.; Rigatti, Lora H.; Windish, Hillarie Plessner; Langton-Webster, Beatrice; Berkman, Clifford E.; Anderson, Carolyn J.

doi:10.1007/s11307-019-01404-8

Cited by 25 publications

(24 citation statements)

References 31 publications

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“…Similar results were recently reported following ex-vivo biodistribution studies in mouse 24 and rat models. 8 Consequently, in this study, salivary glands were not considered as a source organ for dosimetric calculations.…”

Section: Discussionmentioning

confidence: 99%

“…However, it was found that high blood activity levels also increase the dose absorbed by healthy tissues. 7,8 Previously, we reported a PSMA endoradiotherapy agent 177 Lu-scFvD2B, obtained by DOTA conjugation to a singlechain variable fragment of the IgGD2B antibody (scFvD2B) labeled with Lu-177. In vitro studies using LNCaP cells showed a significant higher cell uptake and internalization of 177 Lu-scFvD2B compared with 177 Lu-PSMA-617 and 177 Lu-iPSMA.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Furthermore, the paramagnetic properties and high density of 166 Ho enable visualization by magnetic resonance (MR) and CT imaging (23) There is recent interest in the beta/gamma emitter 177 Lu imaging and dosimetry due to the FDA approval of 177 Lu-DOTATATE (Lutathera) peptide receptor radionuclide therapy (PRRT) for treatment of metastatic gastroenteropancreatic neuroendocrine tumor (gNET) and the use of 177 Lu prostate-specific membrane antigen (PSMA) radioligand therapy for metastatic prostate cancer (24). Both these therapies are administered in 4 consecutive cycles with a fixed administration of 7.4 GBq/cycle (23,25). SPECTbased dosimetry could be used for absorbed dose verification after each cycle, using 177 Lu photon emissions, following guidelines published in a MIRD/EANM joint pamphlet (26).…”

Section: Clinical Dosimetry Methods For Rptmentioning

confidence: 99%

Overview of the First NRG Oncology–National Cancer Institute Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy

et al. 2020

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In 2018, the National Cancer Institute (NCI) and the NRG Oncology partnered for the first time to host a joint Workshop on Systemic Radiopharmaceutical Therapy (RPT) to specifically address issues and strategies of dosimetry for future clinical trials. The workshop focused on (1) current dosimetric approaches for clinical trials, (2) strategies under development that would provide optimal dose reporting, and (3) future desired/optimized approaches for the new and novel emerging radionuclides and carriers in development. In this proceedings, we review the main approaches that are applied clinically to calculate the absorbed dose: These include absorbed doses calculated over a variety of spatial scales including "whole body", organ, sub-organ, and voxel, the latter three all achievable within the Medical Internal Radiation Dose (MIRD) schema (S-value) can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This proceeding will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biological effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We also briefly discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation-when merited by evidence collected during earlyphase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.

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“…To date, PSMA-617 and PSMA I&T are the most commonly used theragnostic PSMA radioligands because they can be radiolabeled with diagnostic, e.g., 68 Ga and 44 Sc for PET and 111 In for SPECT, as well as therapeutic radiometals [ 138 , 139 , 140 , 141 , 142 , 143 , 144 ]. In an attempt to prolong circulation in the blood and therewith, to increase the dose delivered to tumors and the tumor-to-kidney ratio, PSMA ligands have been structurally modified by adding albumin-binding moieties [ 123 , 132 , 145 , 146 , 147 , 148 , 149 , 150 ]. Preclinical and clinical studies are required to demonstrate whether PSMA inhibitors with enhanced albumin binding (HTK01169, PSMA-ALB-56, RPS-074, EB-PSMA-617, CTT1403) can increase the efficacy of PSMA-TRT [ 103 , 146 , 148 , 150 , 151 ].…”

Section: Targeted Radionuclide Therapy Of Prostate Cancermentioning

confidence: 99%

“…In an attempt to prolong circulation in the blood and therewith, to increase the dose delivered to tumors and the tumor-to-kidney ratio, PSMA ligands have been structurally modified by adding albumin-binding moieties [ 123 , 132 , 145 , 146 , 147 , 148 , 149 , 150 ]. Preclinical and clinical studies are required to demonstrate whether PSMA inhibitors with enhanced albumin binding (HTK01169, PSMA-ALB-56, RPS-074, EB-PSMA-617, CTT1403) can increase the efficacy of PSMA-TRT [ 103 , 146 , 148 , 150 , 151 ]. A recently published review provides a comprehensive overview of the current status of selected PSMA inhibitors that have been developed from 1996–2020, emphasizing recent synthetic advances and chemical strategies while highlighting the therapeutic potential and drawbacks of each inhibitor [ 152 ].…”

Section: Targeted Radionuclide Therapy Of Prostate Cancermentioning

confidence: 99%

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

Juzeniene

Stenberg

Bruland

et al. 2021

Cancers

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Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β- therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT.

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Preclinical Dosimetry, Imaging, and Targeted Radionuclide Therapy Studies of Lu-177-Labeled Albumin-Binding, PSMA-Targeted CTT1403

Cited by 25 publications

References 31 publications

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

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

Overview of the First NRG Oncology–National Cancer Institute Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

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Preclinical Dosimetry, Imaging, and Targeted Radionuclide Therapy Studies of Lu-177-Labeled Albumin-Binding, PSMA-Targeted CTT1403

Cited by 25 publications

References 31 publications

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

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

Overview of the First NRG Oncology–National Cancer Institute Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

Contact Info

Product

Resources

About

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

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