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Velikyan, Irina
Alternative names
Publications (10 of 88) Show all publications
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
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
Fani, M., Peitl, P. K. & Velikyan, I. (2017). Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms. Pharmaceuticals, 10(1), Article ID E30.
Open this publication in new window or tab >>Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms
2017 (English)In: Pharmaceuticals, ISSN 1424-8247, E-ISSN 1424-8247, Vol. 10, no 1, article id E30Article, review/survey (Refereed) Published
Abstract [en]

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.

Keywords
CCK2, GIP, GLP-1R, exendin-4, gastrin, neuroendocrine neoplasms, radiolabeled peptides, somatostatin receptor antagonists, theranostics
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-318840 (URN)10.3390/ph10010030 (DOI)000409311900029 ()28295000 (PubMedID)
Available from: 2017-03-30 Created: 2017-03-30 Last updated: 2018-03-16Bibliographically approved
Eriksson, O., Bossart, M., Haack, T., Laitinen, I., Larsen, P., Plettenburg, O., . . . Velikyan, I. (2017). First-in-class PET tracer for the glucagon receptor. Paper presented at 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL. Diabetologia, 60, S400-S400
Open this publication in new window or tab >>First-in-class PET tracer for the glucagon receptor
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2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S400-S400Article in journal, Meeting abstract (Other academic) Published
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-347283 (URN)000408315002205 ()
Conference
53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 11-15, 2017, Lisbon, PORTUGAL
Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2018-04-03Bibliographically approved
Velikyan, I., Rosenström, U. & Eriksson, O. (2017). Fully automated GMP production of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 for clinical use. American Journal of Nuclear Medicine and Molecular Imaging, 7(3), 111-125
Open this publication in new window or tab >>Fully automated GMP production of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 for clinical use
2017 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 7, no 3, p. 111-125Article in journal (Refereed) Published
Abstract [en]

[Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4/PET-CT targeting glucagon like peptide-1 receptor (GLP-1R) has previously demonstrated its potential clinical value for the detection of insulinomas. The production and accessibility of this radiopharmaceutical is one of the critical factors in realization of clinical trials and routine clinical examinations. Previously, the radiopharmaceutical was prepared manually, however larger scale of clinical trials and healthcare requires automation of the production process in order to limit the operator radiation dose as well as improve tracer manufacturing robustness and on-line documentation for enhanced good manufacturing practice (GMP) compliance. A method for Ga-68-labelling of DO3A-VS-Cys(40)-Exendin-4 on a commercially available synthesis platform was developed. Equipment such as Ge-68/Ga-68 generator, synthesis platform, and disposable cassettes for Ga-68-labelling used in the study was purchased from Eckert & Ziegler. DO3A-VS-Cys(40)-Exendin-4 was synthesized in-house. The parameters such as time, temperature, precursor concentration, radical scavenger, buffer concentration, pH, product purification step were investigated and optimised. Reproducible and GMP compliant automated production of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 was developed. Exendin-4 comprising methionine amino acid residue was prone to oxidation which was strongly influenced by the elevated temperature, radioactivity amount, and precursor concentration. The suppression of the oxidative radiolysis was achieved by addition of ethanol, dihydroxybenzoic acid and ascorbic acid to the reaction buffer as well as by optimizing heating temperature. The non-decay corrected radiochemical yield was 43 +/- 2% with radiochemical purity of over 90% wherein the individual impurity signals in HPLC chromatogram did not exceed 5%. Automated production and quality control methods were established for paving the pathway for broader clinical use of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4.

Keywords
Exendin-4, Insulinoma, GLP-1, GMP, Gallium-68, automation
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-335532 (URN)000409370800002 ()28721305 (PubMedID)
Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2017-12-08Bibliographically approved
Haylock, A.-K., Nilvebrant, J., Mortensen, A., Velikyan, I., Nestor, M. & Falk, R. (2017). Generation and evaluation of antibody agents for molecular imaging of CD44v6-expressing cancers. OncoTarget, 8(39), 65152-65170
Open this publication in new window or tab >>Generation and evaluation of antibody agents for molecular imaging of CD44v6-expressing cancers
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 39, p. 65152-65170Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
scFv, recombinant antibody formats, CD44v6, squamous cell carcinoma, molecular imaging
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-335192 (URN)10.18632/oncotarget.17996 (DOI)000410291200039 ()29029420 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/1080, CAN 2015/385Swedish Research Council, 2013-30876-104113-30, 637-2013-468Swedish Society for Medical Research (SSMF)Knut and Alice Wallenberg Foundation, 2008.0133
Note

Marika Nestor and Ronny Falk shared senior authorship.

Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2017-12-08Bibliographically approved
Sandberg, D. T., Tolmachev, V., Velikyan, I., Olofsson, H., Wennborg, A., Feldwisch, J., . . . Sörensen, J. (2017). Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT.. European Journal of Nuclear Medicine and Molecular Imaging, 44(8), 1337-1346
Open this publication in new window or tab >>Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT.
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2017 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, no 8, p. 1337-1346Article in journal (Refereed) Published
Abstract [en]

PURPOSE: In phase I/II-studies radiolabelled ABY-025 Affibody molecules identified human epidermal growth factor receptor 2 (HER2) expression in breast cancer metastases using PET and SPECT imaging. Here, we wanted to investigate the utility of a simple intra-image normalization using tumour-to-reference tissue-ratio (T/R) as a HER2 status discrimination strategy to overcome potential issues related to cross-calibration of scanning devices.

METHODS: Twenty-three women with pre-diagnosed HER2-positive/negative metastasized breast cancer were scanned with [(111)In]-ABY-025 SPECT/CT (n = 7) or [(68)Ga]-ABY-025 PET/CT (n = 16). Uptake was measured in all metastases and in normal spleen, lung, liver, muscle, and blood pool. Normal tissue uptake variation and T/R-ratios were established for various time points and for two different doses of injected peptide from a total of 94 whole-body image acquisitions. Immunohistochemistry (IHC) was used to verify HER2 expression in 28 biopsied metastases. T/R-ratios were compared to IHC findings to establish the best reference tissue for each modality and each imaging time-point. The impact of shed HER2 in serum was investigated.

RESULTS: Spleen was the best reference tissue across modalities, followed by blood pool and lung. Spleen-T/R was highly correlated to PET SUV in metastases after 2 h (r = 0.96, P < 0.001) and reached an accuracy of 100% for discriminating IHC HER2-positive and negative metastases at 4 h (PET) and 24 h (SPECT) after injection. In a single case, shed HER2 resulted in intense tracer retention in blood. In the remaining patients shed HER2 was elevated, but without significant impact on ABY-025 biodistribution.

CONCLUSION: T/R-ratios using spleen as reference tissue accurately quantify HER2 expression with radiolabelled ABY-025 imaging in breast cancer metastases with SPECT and PET. Tracer binding to shed HER2 in serum might affect quantification in the extreme case.

Keywords
Affibody, HER2-receptor, PET, SPECT, Shedding, T/R
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317746 (URN)10.1007/s00259-017-3650-3 (DOI)000403468900012 ()28261749 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-02-28Bibliographically approved
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