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Träfflista för sökning "WFRF:(Velikyan Irina 1966 ) "

Sökning: WFRF:(Velikyan Irina 1966 )

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  • [1]2345Nästa
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1.
  • Eriksson, Olof, et al. (författare)
  • Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates
  • 2019
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [Ga-68]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [Ga-68]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67 mu g/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [Ga-68]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [Ga-68]GaDO3A-S01-GCG binding in liver. [Ga-68]Ga-DO3A-S01-GCG bound to liver in vivo in a dose-dependent manner. Negligible peptide mass effect was observed for DO3A-S01-GCG doses <0.2 mu g/kg. In vivo K-d for [Ga-68]Ga-DO3A-S01-GCG corresponded to 0.7 mu g/kg, which indicates high potency. The test-retest reproducibility for [Ga-68]Ga-DO3A-S01-GCG binding in liver was 5.7 +/- 7.9%. Pre-treatment with 1-GCG, an acylated glucagon agonist, resulted in a GCGR occupancy of 61.5 +/- 9.1% in liver. Predicted human radiation dosimetry would allow for repeated annual [Ga-68]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [Ga-68]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy.
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2.
  • Haylock, Anna-Karin, et al. (författare)
  • Generation and evaluation of antibody agents for molecular imaging of CD44v6-expressing cancers
  • 2017
  • Ingår i: OncoTarget. - : Impact Journals LLC. - 1949-2553 .- 1949-2553. ; 8:39, s. 65152-65170
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: The aim of this study was to generate and characterize scFv antibodies directed to human CD44v6, as well as to radiolabel and evaluate top candidates in vitro and in vivo for their potential use in CD44v6-targeted molecular imaging in cancer patients.Materials and methods: Phage display selections were used to isolate CD44v6-specific scFvs. A chain shuffling strategy was employed for affinity maturation based on a set of CD44v6-specific first-generation clones. Two second-generation scFv clones were then chosen for labeling with 111In or 125I and assessed for CD44v6-specific binding on cultured tumor cells. In vivo uptake and distribution was evaluated in tumor-bearing mice using a dual tumor model. Finally, a proof-of-concept small animal PET-CT study was performed on one of the candidates labeled with 124I.Results: Two affinity-matured clones, CD44v6-scFv-A11 and CD44v6-scFv-H12, displayed promising binding kinetics. Seven out of eight radiolabeled conjugates demonstrated CD44v6-specific binding. In vivo studies on selected candidates demonstrated very advantageous tumor-to-organ ratios, in particular for iodinated conjugates, where 125I-labeled scFvs exhibited favorable kinetics and tumor-to-blood ratios above five already at 24 hours p. i.. The small animal PET-CT study using 124I-labeled CD44v6-scFv-H12 was in line with the biodistribution data, clearly visualizing the high CD44v6-expressing tumor.Conclusion: The single chain fragments, CD44v6-scFv-A11 and CD44v6-scFv-H12 specifically bind to CD44v6, and the radiolabeled counterparts provide high tumor-to-blood ratios and fast clearance from organs and blood. We conclude that radioiodinated CD44v6-scFv-A11 and CD44v6-scFv-H12 possess features highly suitable for stringent molecular imaging.
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3.
  • Alhuseinalkhudhur, Ali, et al. (författare)
  • Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer
  • 2020
  • Ingår i: EJNMMI Research. - : SPRINGEROPEN. - 2191-219X .- 2191-219X. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: High expression of human epidermal growth factor receptor type 2 (HER2) represents an aggressive subtype of breast cancer. Anti-HER2 treatment requires a theragnostic approach wherein sufficiently high receptor expression in biopsy material is mandatory. Heterogeneity and discordance of HER2 expression between primary tumour and metastases, as well as within a lesion, present a complication for the treatment and require multiple biopsies. Molecular imaging using the HER2-targeting Affibody peptide ABY-025 radiolabelled with Ga-68-gallium for PET/CT is currently under investigation as a non-invasive tool for whole-body evaluation of metastatic HER2 expression. Initial studies demonstrated a high correlation between Ga-68-ABY-025 standardized uptake values (SUVs) and histopathology. However, detecting small liver lesions might be compromised by high background uptake. This study aimed to explore the applicability of kinetic modelling and parametric image analysis for absolute quantification of Ga-68-ABY-025 uptake and HER2-receptor expression and how that relates to static SUVs.Methods: Dynamic Ga-68-ABY-025 PET of the upper abdomen was performed 0-45 min post-injection in 16 patients with metastatic breast cancer. Five patients underwent two examinations to test reproducibility. Parametric images of tracer delivery (K-1) and irreversible binding (K-i) were created with an irreversible two-tissue compartment model and Patlak graphical analysis using an image-derived input function from the descending aorta. A volume of interest (VOI)-based analysis was performed to validate parametric images. SUVs were calculated from 2 h and 4 h post-injection static whole-body images and compared to K-i.Results: Characterization of HER2 expression in smaller liver metastases was improved using parametric images. K-i values from parametric images agreed very well with VOI-based gold standard (R-2 > 0.99, p < 0.001). SUVs of metastases at 2 h and 4 h post-injection were highly correlated with K-i values from both the two-tissue compartment model and Patlak method (R-2 = 0.87 and 0.95, both p < 0.001). Ga-68-ABY-025 PET yielded high test-retest reliability (relative repeatability coefficient for Patlak 30% and for the two-tissue compartment model 47%).Conclusion: Ga-68-ABY-025 binding in HER2-positive metastases was well characterized by irreversible two-tissue compartment model wherein K-i highly correlated with SUVs at 2 and 4 h. Dynamic scanning with parametric image formation can be used to evaluate metastatic HER2 expression accurately.
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5.
  • Eriksson, Olof, et al. (författare)
  • Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography
  • 2021
  • Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 70:4, s. 842-853
  • Tidskriftsartikel (refereegranskat)abstract
    • Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with Ga-68. The resulting PET tracer [Ga-68]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [Ga-68]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [Ga-68]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [Ga-68]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [Ga-68]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [Ga-68]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
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7.
  • Eriksson, Olof, et al. (författare)
  • Imaging of the Glucagon Receptor in Subjects with Type 2 Diabetes
  • 2021
  • Ingår i: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE INC. - 0161-5505 .- 1535-5667. ; 62:6, s. 833-838
  • Tidskriftsartikel (refereegranskat)abstract
    • Despite the importance of the glucagon receptor (GCGR) in disease and in pharmaceutical drug development, there is a lack of specific and sensitive biomarkers of its activation in humans. The PET radioligand Ga-68-DO3A-VS-Tuna-2 (Ga-68-Tuna-2) was developed to yield a noninvasive imaging marker for GCGR target distribution and drug target engagement in humans. Methods: The biodistribution and dosimetry of Ga-68-Tuna-2 was assessed by PET/CT in 13 individuals with type 2 diabetes as part of a clinical study assessing the occupancy of the dual GCGR/glucagon like peptide-1 receptor agonist SAR425899. Binding of Ga-68-Tuna-2 in liver and reference tissues was evaluated and correlated to biometrics (e.g., weight or body mass index) or other biomarkers (e.g., plasma glucagon levels). Results: Ga-68-Tuna-2 binding was seen primarily in the liver, which is in line with the strong expression of GCGR on hepatocytes. The kidneys demonstrated high excretion-related retention, whereas all other tissue demonstrated rapid washout. The SUV55 (min) (SUV during the last 10-min time frame, 50-60 min after administration) uptake endpoint was sensitive to endogenous levels of glucagon. Ga-68-Tuna-2 exhibited a safe dosimetry profile and no adverse events after intravenous administration. Conclusion: Ga-68-Tuna-2 can be used for safe and accurate assessment of the GCGR in human. It may serve as an important tool in understanding the in vivo pharmacology of novel drugs engaging the GCGR.
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8.
  • Eriksson, Olof, et al. (författare)
  • Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes
  • 2020
  • Ingår i: Scientific Reports. - : NATURE RESEARCH. - 2045-2322. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Patients with T2D were examined by [Ga-68]Ga-DO3A-Tuna-2 and [Ga-68]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. Follow up PET examinations were performed after 17 (GCGR) and 20 (GLP-1R) days of treatment with SAR425899, to assess the occupancy at each receptor. Six out of 13 included patients prematurely discontinued the study due to adverse events. SAR425899 at a dose of 0.2 mg daily demonstrated an average GCGR occupancy of 11.2 +/- 14.4% (SD) in N=5 patients and a GLP1R occupancy of 49.9 +/- 13.3%. Fasting Plasma Glucose levels (-3.30 +/- 1.14 mmol/L) and body weight (-3.87 +/- 0.87%) were lowered under treatment with SAR425899. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET.
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9.
  • Eriksson, Olof, et al. (författare)
  • Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin4
  • 2017
  • Ingår i: Acta Diabetologica. - 0940-5429 .- 1432-5233. ; 54:11, s. 1039-1045
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: Radiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed.METHODS: -Exendin4 Positron Emission Tomography (PET) in the same species. In vitro, ex vivo, and in vivo data formed the basis for calculating the theoretical in vivo contribution of each pancreatic compartment.RESULTS: -Exendin4.CONCLUSIONS: IPR as well as the exocrine GLP-1R density is the main determinants of the species variability in pancreatic uptake. Thus, the IPR in human is an important factor for assessing the potential of GLP-1R as an imaging biomarker for pancreatic beta cells.
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10.
  • Fani, Melpomeni, et al. (författare)
  • Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms
  • 2017
  • Ingår i: Pharmaceuticals. - 1424-8247 .- 1424-8247. ; 10:1
  • Forskningsöversikt (refereegranskat)abstract
    • Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors.
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  • Resultat 1-10 av 42
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