Dataset Information

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177.

ABSTRACT: Targeting of cholecystokinin-2 receptor (CCK2R) expressing tumors using radiolabeled minigastrin (MG) analogs is hampered by rapid digestion of the linear peptide in vivo. In this study, a new MG analog stabilized against enzymatic degradation was investigated in preclinical studies to characterize the metabolites formed in vivo. The new MG analog DOTA-DGlu-Pro-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2 comprising site-specific amino acid substitutions in position 2, 6 and 8 and different possible metabolites thereof were synthesized. The receptor interaction of the peptide and selected metabolites was evaluated in a CCK2R-expressing cell line. The enzymatic stability of the 177Lu-labeled peptide analog was evaluated in vitro in different media as well as in BALB/c mice up to 1 h after injection and the metabolites were identified based on radio-HPLC analysis. The new radiopeptide showed a highly increased stability in vivo with >56% intact radiopeptide in the blood of BALB/c mice 1 h after injection. High CCK2R affinity and cell uptake was confirmed only for the intact peptide, whereas enzymatic cleavage within the receptor specific C-terminal amino acid sequence resulted in complete loss of affinity and cell uptake. A favorable biodistribution profile was observed in BALB/c mice with low background activity, preferential renal excretion and prolonged uptake in CCK2R-expressing tissues. The novel stabilized MG analog shows high potential for diagnostic and therapeutic use. The radiometabolites characterized give new insights into the enzymatic degradation in vivo.

SUBMITTER: Hormann AA

PROVIDER: S-EPMC7583830 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177.

Hörmann Anton Amadeus AA Klingler Maximilian M Rezaeianpour Maliheh M Hörmann Nikolas N Gust Ronald R Shahhosseini Soraya S Guggenberg Elisabeth von EV

Molecules (Basel, Switzerland) 20201008 19

Targeting of cholecystokinin-2 receptor (CCK2R) expressing tumors using radiolabeled minigastrin (MG) analogs is hampered by rapid digestion of the linear peptide in vivo. In this study, a new MG analog stabilized against enzymatic degradation was investigated in preclinical studies to characterize the metabolites formed in vivo. The new MG analog DOTA-DGlu-Pro-Tyr-Gly-Trp-(<i>N</i>-Me)Nle-Asp-1Nal-NH<sub>2</sub> comprising site-specific amino acid substitutions in position 2, 6 and 8 and differ ...[more]

PMID: 33049999

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Project description:BackgroundPSMA-TO-1 ("Tumor-Optimized-1") is a novel PSMA ligand with longer circulation time than PSMA-617. We compared the biodistribution in subcutaneous tumor-bearing mice of PSMA-TO-1, PSMA-617 and PSMA-11 when labeled with 68Ga and 177Lu, and the survival after treatment with 225Ac-PSMA-TO-1/-617 in a murine model of disseminated prostate cancer. We also report dosimetry data of 177Lu-PSMA-TO1/-617 in prostate cancer patients.MethodsFirst, PET images of 68Ga-PSMA-TO-1/-617/-11 were acquired on consecutive days in three mice bearing subcutaneous C4-2 xenografts. Second, 50 subcutaneous tumor-bearing mice received either 30 MBq of 177Lu-PSMA-617 or 177Lu-PSMA-TO-1 and were sacrificed at 1, 4, 24, 48 and 168 h for ex vivo gamma counting and biodistribution. Third, mice bearing disseminated lesions via intracardiac inoculation were treated with either 40 kBq of 225Ac-PSMA-617, 225Ac-PSMA-TO-1, or remained untreated and followed for survival. Additionally, 3 metastatic castration-resistant prostate cancer patients received 500 MBq of 177Lu-PSMA-TO-1 under compassionate use for dosimetry purposes. Planar images with an additional SPECT/CT acquisition were acquired for dosimetry calculations.ResultsTumor uptake measured by PET imaging of 68Ga-labeled agents in mice was highest using PSMA-617, followed by PSMA-TO-1 and PSMA-11. 177Lu-PSMA tumor uptake measured by ex vivo gamma counting at subsequent time points tended to be greater for PSMA-TO-1 up to 1 week following treatment (p > 0.13 at all time points). This was, however, accompanied by increased kidney uptake and a 26-fold higher kidney dose of PSMA-TO-1 compared with PSMA-617 in mice. Mice treated with a single-cycle 225Ac-PSMA-TO-1 survived longer than those treated with 225Ac-PSMA-617 and untreated mice, respectively (17.8, 14.5 and 7.7 weeks, respectively; p < 0.0001). Kidney, salivary gland, bone marrow and mean ± SD tumor dose coefficients (Gy/GBq) for 177Lu-PSMA-TO-1 in patients #01/#02/#03 were 2.5/2.4/3.0, 1.0/2.5/2.3, 0.14/0.11/0.10 and 0.42 ± 0.03/4.45 ± 0.07/1.8 ± 0.57, respectively.ConclusionsPSMA-TO-1 tumor uptake tended to be greater than that of PSMA-617 in both preclinical and clinical settings. Mice treated with 225Ac-PSMA-TO-1 conferred a significant survival benefit compared to 225Ac-PSMA-617 despite the accompanying increased kidney uptake. In humans, PSMA-TO-1 dosimetry estimates suggest increased tumor absorbed doses; however, the kidneys, salivary glands and bone marrow are also exposed to higher radiation doses. Thus, additional preclinical studies are needed before further clinical use.

Project description:PurposeA series of radiotracers targeting fibroblast activation protein (FAP) with great pharmacokinetics have been developed for cancer diagnosis and therapy. Nevertheless, the use of dominant PET tracers, gallium-68-labeled FAPI derivatives, was limited by the short nuclide half-life and production scale, and the therapeutic tracers exhibited rapid clearance and insufficient tumor retention. In this study, we developed a FAP targeting ligand, LuFL, containing organosilicon-based fluoride acceptor (SiFA) and DOTAGA chelator, capable of labeling fluorine-18 and lutetium-177 in one molecular with simple and highly efficient labeling procedure, to achieve cancer theranostics.MethodsThe precursor LuFL (20) and [natLu]Lu-LuFL (21) were successfully synthesized and labeled with fluorine-18 and lutetium-177 using a simple procedure. A series of cellular assays were performed to characterize the binding affinity and FAP specificity. PET imaging, SPECT imaging, and biodistribution studies were conducted to evaluate pharmacokinetics in HT-1080-FAP tumor-bearing nude mice. A comparison study of [177Lu]Lu-LuFL ([177Lu]21) and [177Lu]Lu-FAPI-04 was carried out in HT-1080-FAP xenografts to determine the cancer therapeutic efficacy.ResultsLuFL (20) and [natLu]Lu-LuFL (21) demonstrated excellent binding affinity towards FAP (IC50: 2.29 ± 1.12 nM and 2.53 ± 1.87 nM), compared to that of FAPI-04 (IC50: 6.69 ± 0.88 nM). In vitro cellular studies showed that 18F-/177Lu-labeled 21 displayed high specific uptake and internalization in HT-1080-FAP cells. Micro-PET, SPECT imaging and biodistribution studies with [18F]/[177Lu]21 revealed higher tumor uptake and longer tumor retention than those of [68 Ga]/[177Lu]Ga/Lu-FAPI-04. The radionuclide therapy studies showed significantly greater inhibition of tumor growth for the [177Lu]21 group, than for the control group and the [177Lu]Lu-FAPI-04 group.ConclusionThe novel FAPI-based radiotracer containing SiFA and DOTAGA was developed as a theranostics radiopharmaceutical with simple and short labeling process, and showed promising properties including higher cellular uptake, better FAP binding affinity, higher tumor uptake and prolong retention compared to FAPI-04. Preliminary experiments with 18F- and 177Lu-labeled 21 showed promising tumor imaging properties and favorable anti-tumor efficacy.

Project description:Lessons learnedHyperfractionation of lutetium-177 (177 Lu)-J591 for patients with metastatic castration-resistant prostate cancer did not appear to have any additional advantage over the single dose 177 Lu-J591 or fractionated two-dose 177 Lu-J591 therapy. Definite conclusions were challenging because of the small sample size of this study, and so further studies are needed to evaluate the viability of the hypothesis. On the basis of available data, a registration study of 177 Lu-J591 (also known as TLX591) is planned and will use the two-dose fractionation schedule (Telix Pharma Q3 2019 update https://telixpharma.com/news-media/).BackgroundPhase I and II single-dose studies of lutetium-177 (177 Lu)-J591, a radio-labeled antibody binding prostate-specific membrane antigen (PSMA), demonstrated safety and efficacy with dose response. Modest dose fractionation of 177 Lu-J591 (2 doses) has less myelosuppression per similar cumulative dose, allowing higher doses to be administered safely. We hypothesized that additional dose fractionation would allow a higher cumulative dose, potentially with less toxicity and more efficacy.MethodsMen with progressive metastatic castration-resistant prostate cancer and adequate organ function were enrolled. 177 Lu-J591 was administered at 25 mCi/m2 every 2 weeks until the emergence of related grade 2 toxicity. 177 Lu-J591 imaging was performed and circulating tumor cell (CTC) counts were measured before and after treatment along with standard monitoring.ResultsSix subjects in a single cohort, with a median age of 68.6 years, were enrolled. Patients received three to six doses (cumulative 75-150 mCi/m2 ). Two (33%) patients had >30% prostate-specific antigen (PSA) decline and three (50%) had CTC count decline. Two (33%) experienced grade (Gr) 4 neutropenia (without fever), three (50%) had Gr 4 thrombocytopenia (without hemorrhage), and two (33%) required platelet transfusions. Following hematological improvement, two patients developed worsening cytopenia during prostate cancer progression; bone marrow biopsies revealed infiltrative tumor replacing normal marrow elements without myelodysplasia. Targeting of known disease sites was seen on planar imaging in all.ConclusionHyperfractionation of 177 Lu-J591 is feasible but does not seem to have significant advantages over the two-dose fractionation regimen.

Project description:BackgroundMetastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (177Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.MethodsWe conducted an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)-labeled PSMA-11 positron-emission tomographic-computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.ResultsFrom June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. 177Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). All the key secondary end points significantly favored 177Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.ConclusionsRadioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664.).

Dataset Information

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177.

Publications

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177.

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