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Velikyan, Irina
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Publications (10 of 95) Show all publications
Velikyan, I., Schweighoefer, P., Feldwisch, J., Seemann, J., Frejd, F. Y., Lindman, H. & Sörensen, J. (2019). Diagnostic HER2-binding radiopharmaceutical, [Ga-68]Ga-ABY-025, for routine clinical use in breast cancer patients. American Journal of Nuclear Medicine and Molecular Imaging, 9(1), 12-23
Open this publication in new window or tab >>Diagnostic HER2-binding radiopharmaceutical, [Ga-68]Ga-ABY-025, for routine clinical use in breast cancer patients
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2019 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 9, no 1, p. 12-23Article in journal (Refereed) Published
Abstract [en]

[Ga-68]Ga-ABY-025/PET-CT targeting human epidermal growth factor receptor type 2 (HER2) has demonstrated its potential clinical value for the detection and quantification of HER2 in a phase I clinical study with breast cancer patients. Previously, the radiopharmaceutical was prepared manually, however larger scale of multicenter clinical trials and routine healthcare requires automation of the production process to limit the operator radiation dose, improve tracer manufacturing robustness, and provide on-line documentation for good manufacturing practice (GMP) compliance. The production of [Ga-68]Ga-ABY-025 was implemented on the Modular-Lab PharmTrace synthesis platform (Eckert & Ziegler) and disposable cassettes were developed. Pharmaceutical grade Ge-68/Ga-68 generator (GalliaPharm (R)) was used in the study. The active pharmaceutical ingredient starting material ABY-025 (GMP grade) was provided by Affibody AB. The patient examinations were conducted using a Discovery MI PET/CT scanner (20 cm FOV, GE Healthcare). Reproducible and GMP compliant fully automated production of [Ga-68]Ga-ABY-025 was developed. The radiochemical purity of the product was 98.7 +/- 0.6% with total peptide content of 315 +/- 15 mu g (n = 3). Radionuclidic purity, sterility, endotoxin content, residual solvent content, and sterile filter integrity were controlled and met acceptance criteria. The product was stable at ambient temperature for at least 2 h. The primary tumor and metastasis were detected with SUVmax values of 8.3 and 16.0, respectively. Automated production of [Ga-68]Ga-ABY-025 was established and the process was validated enabling standardized multicenter phase II and III clinical trials and routine clinical use. Patient examinations conformed to the radiopharmaceutical biodistribution observed in the previous phase I study.

Place, publisher, year, edition, pages
E-CENTURY PUBLISHING CORP, 2019
Keywords
Affibody, breast cancer, clinical study, HER2, GMP, gallium-68
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-379777 (URN)000460442600002 ()
Funder
Swedish Cancer SocietyThe Breast Cancer Foundation
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2019-03-21Bibliographically approved
Velikyan, I., Haack, T., Bossart, M., Evers, A., Laitinen, I., Larsen, P., . . . Eriksson, O. (2019). First-in-class positron emission tomography tracer for the glucagon receptor. EJNMMI Research, 9, Article ID 17.
Open this publication in new window or tab >>First-in-class positron emission tomography tracer for the glucagon receptor
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2019 (English)In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 9, article id 17Article in journal (Refereed) Published
Abstract [en]

The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement.

Methods: Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [68Ga]Ga-DO3A-S01-GCG and [68Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat.

Results: [68Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [68Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals.

Conclusion: [68Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans.

Keywords
Glucagon, GCG, GLP-1 receptor, Dual agonist, Type 2 diabetes
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-378994 (URN)10.1186/s13550-019-0482-0 (DOI)000459043900002 ()30771019 (PubMedID)
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-03-19Bibliographically approved
Lindström, E., Velikyan, I., Regula, N. K., Alhuseinalkhudhur, A., Sundin, A., Sörensen, J. & Lubberink, M. (2019). Regularized reconstruction of digital time-of-flight Ga-68-PSMA-11 PET/CT for the detection of recurrent disease in prostate cancer patients. Theranostics, 9(12), 3476-3484
Open this publication in new window or tab >>Regularized reconstruction of digital time-of-flight Ga-68-PSMA-11 PET/CT for the detection of recurrent disease in prostate cancer patients
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2019 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 9, no 12, p. 3476-3484Article in journal (Refereed) Published
Abstract [en]

Accurate localization of recurrent prostate cancer (PCa) is critical, especially if curative therapy is intended. With the aim to optimize target-to-background uptake ratio in Ga-68-PSMA-11 PET, we investigated the image quality and quantitative measures of regularized reconstruction by block-sequential regularized expectation maximization (BSREM).

Methods:

The study encompassed retrospective reconstruction and analysis of 20 digital time-of-flight (TOF) PET/CT examinations acquired 60 min post injection of 2 MBq/kg of Ga-68-PSMA-11 in PCa patients with biochemical relapse after primary treatment. Reconstruction by ordered-subsets expectation maximization (OSEM; 3 iterations, 16 subsets, 5 mm gaussian postprocessing filter) and BSREM (beta-values of 100-1600) were used, both including TOF and point spread function (PSF) recovery. Background variability (BV) was measured by placing a spherical volume of interest in the right liver lobe and defined as the standard deviation divided by the mean standardized uptake value (SUV). The image quality was evaluated in terms of signal-to-noise ratio (SNR) and signal-to-background ratio (SBR), using SUVmax of the lesions. A visual assessment was performed by four observers.

Results:

OSEM reconstruction produced images with a BV of 15%, whereas BSREM with a beta-value above 300 resulted in lower BVs than OSEM (36% with beta 100, 8% with beta 1300). Decreasing the acquisition duration from 2 to 1 and 0.5 min per bed position increased BV for both reconstruction methods, although BSREM with beta-values equal to or higher than 800 and 1200, respectively, kept the BV below 15%. In comparison of BSREM with OSEM, the mean SNR improved by 25 to 66% with an increasing beta-value in the range of 200-1300, whereas the mean SBR decreased with an increasing beta-value, ranging from 0 to 125% with a beta-value of 100 and 900, respectively. Decreased acquisition duration resulted in beta-values of 800 to 1000 and 1200 to 1400 for 1 and 0.5 min per bed position, respectively, producing improved image quality measures compared with OSEM at a full acquisition duration of 2 min per bed position. The observer study showed a slight overall preference for BSREM beta 900 although the interobserver variability was high.

Conclusion:

BSREM image reconstruction with beta-values in the range of 400-900 resulted in lower BV and similar or improved SNR and SBR in comparison with OSEM.

Keywords
Ga-68-PSMA-11, prostate cancer, PET/CT, image reconstruction, BSREM, interobserver variability
National Category
Medical Image Processing
Identifiers
urn:nbn:se:uu:diva-388045 (URN)10.7150/thno.31970 (DOI)000469953000006 ()
Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Jahn, U., Ilan, E., Sandström, M., Garske-Román, U., Velikyan, I., Fröss-Baron, K., . . . Sundin, A. (2018). 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy; Gender Differences in Small Intestinal and Pancreatic Neuroendocrine Tumors. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S61-S62
Open this publication in new window or tab >>177Lu-DOTATATE Peptide Receptor Radionuclide Therapy; Gender Differences in Small Intestinal and Pancreatic Neuroendocrine Tumors
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S61-S62Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372962 (URN)000449266200098 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved
Ilan, E., Lubberink, M., Sandström, M., Jahn, U., Velikyan, I., Andersson, C., . . . Sundin, A. (2018). Comparison of Ga-68-DOTATATE and Lu-177-DOTATATE kinetics in neuroendocrine tumors. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S276-S277
Open this publication in new window or tab >>Comparison of Ga-68-DOTATATE and Lu-177-DOTATATE kinetics in neuroendocrine tumors
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S276-S277Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372961 (URN)000449266202159 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved
Monazzam, A., Lau, J., Velikyan, I., Li, S.-C., Razmara, M., Rosenström, U., . . . Skogseid, B. (2018). Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET. Scientific Reports, 8, Article ID 748.
Open this publication in new window or tab >>Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 748Article in journal (Refereed) Published
Abstract [en]

Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-342327 (URN)10.1038/s41598-017-18855-0 (DOI)000422637200007 ()29335487 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-28Bibliographically approved
Wilking, H., Ilan, E., Sandström, M., Andersson, C., Öst, A., Velikyan, I., . . . Lubberink, M. (2018). In-vivo stability of 177Lu-DOTATATE during peptide receptor radionuclide therapy. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY.. European Journal of Nuclear Medicine and Molecular Imaging, 45(Supplement 1), S592-S592
Open this publication in new window or tab >>In-vivo stability of 177Lu-DOTATATE during peptide receptor radionuclide therapy
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no Supplement 1, p. S592-S592Article in journal, Meeting abstract (Other academic) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-373341 (URN)10.1007/s00259-018-4148-3 (DOI)000449266205174 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY.
Note

Meeting Abstract: EP-0729

Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Alhuseinalkhudhur, A., Lubberink, M., Velikyan, I., Tolmachev, V., Frejd, F., Feldwisch, J., . . . Sörensen, J. (2018). Kinetic Analysis of the HER2-binding ABY-025 Affibody Using Dynamic PET in Patients with Metastatic Breast Cancer. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S457-S457
Open this publication in new window or tab >>Kinetic Analysis of the HER2-binding ABY-025 Affibody Using Dynamic PET in Patients with Metastatic Breast Cancer
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S457-S457Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372956 (URN)000449266204116 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-01-24Bibliographically approved
Velikyan, I. & Lindhe, O. (2018). Preparation and evaluation of a Ga-68-labeled RGD-containing octapeptide for noninvasive imaging of angiogenesis: biodistribution in non-human primate. American Journal of Nuclear Medicine and Molecular Imaging, 8(1), 15-31
Open this publication in new window or tab >>Preparation and evaluation of a Ga-68-labeled RGD-containing octapeptide for noninvasive imaging of angiogenesis: biodistribution in non-human primate
2018 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 8, no 1, p. 15-31Article in journal (Refereed) Published
Abstract [en]

Monitoring general disease marker such as angiogenesis may contribute to the development of personalized medicine and improve therapy outcome. Readily availability of positron emitter based imaging agents providing quantification would expand clinical positron emission tomography (PET) applications. Generator produced Ga-68 provides PET images of high resolution and the half-life time frame is compatible with the pharmacokinetics of small peptides comprising arginine-glycine-aspartic acid (RGD) sequence specific to alpha(v)beta(3) integrin receptors. The main objective of this study was to develop a method for Ga-68-labeling of RGD containing bicyclic octapeptide ([Ga-68]Ga-DOTA-RGD) with high specific radioactivity and preclinically assess its imaging potential. DOTA-RGD was labeled using generator eluate preconcentration technique and microwave heating. The binding and organ distribution properties of [Ga-68]Ga-DOTA-RGD were tested in vitro by autoradiography of frozen tumor sections, and in vivo in mice carrying a Lewis Lung carcinoma graft (LL2), and in non-human primate (NHP). Another peptide with aspartic acid-glycine-phenylalanine sequence was used as a negative control. The full Ga-68 radioactivity eluted from two generators was quantitatively incorporated into 3-8 nanomoles of the peptide conjugates. The target binding specificity was confirmed by blocking experiments. The specific uptake in the LL2 mice model was observed in vivo and confirmed in the corresponding ex vivo biodistribution experiments. Increased accumulation of the radioactivity was detected in the wall of the uterus of the female NHP probably indicating neovascularization. [Ga-68]Ga-DOTA-RGD demonstrated potential for the imaging of angiogenesis.

Keywords
Ga-68, RGD, PET, animal PET, angiogenesis, cancer, endometriosis, Lewis lung carcinoma, organ distribution, frozen section autoradiography, whole body autoradiography
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-350549 (URN)000426585200002 ()29531858 (PubMedID)
Available from: 2018-05-21 Created: 2018-05-21 Last updated: 2018-05-21Bibliographically approved
Velikyan, I. (2018). Prospective of Ga-68 Radionuclide Contribution to the Development of Imaging Agents for Infection and Inflammation. Contrast Media & Molecular Imaging, Article ID UNSP 9713691.
Open this publication in new window or tab >>Prospective of Ga-68 Radionuclide Contribution to the Development of Imaging Agents for Infection and Inflammation
2018 (English)In: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, article id UNSP 9713691Article, review/survey (Refereed) Published
Abstract [en]

During the last decade, the utilization of Ga-68 for the development of imaging agents has increased considerably with the leading position in the oncology. The imaging of infection and inflammation is lagging despite strong unmet medical needs. This review presents the potential routes for the development of Ga-68-based agents for the imaging and quantification of infection and inflammation in various diseases and connection of the diagnosis to the treatment for the individualized patient management.

Place, publisher, year, edition, pages
WILEY-HINDAWI, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-386357 (URN)10.1155/2018/9713691 (DOI)000422779600001 ()29531507 (PubMedID)
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
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