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  • 1.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Hao
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Ding, Haozhong
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Edqvist, Per-Henrik D
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjorn
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 288, p. 84-95Article in journal (Refereed)
    Abstract [en]

    Patients with HER2-positive tumors often suffer resistance to therapy, warranting development of novel treatment modalities. Affibody molecules are small affinity proteins which can be engineered to bind to desired targets. They have in recent years been found to allow precise targeting of cancer specific molecular signatures such as the HER2 receptor. In this study, we have investigated the potential of an affibody molecule targeting HER2, Z(HER2:2891), conjugated with the cytotoxic maytansine derivate MC-DM1, for targeted cancer therapy. Z(HER2:2891) was expressed as a monomer (Z(HER2:2891)), dimer ((Z(HER2:2891)) 2) and dimer with an albumin binding domain (ABD) for half-life extension ((Z(HER2:2891)) 2-ABD). All proteins had a unique C-terminal cysteine that could be used for efficient and site-specific conjugation with MC-DM1. The resulting affibody drug conjugates were potent cytotoxic molecules for human cells over-expressing HER2, with sub-nanomolar IC50-values similar to trastuzumab emtansine, and did not affect cells with low HER2 expression. A biodistribution study of a radiolabeled version of (Z(HER2:2891))(2)-ABD-MC-DM1, showed that it was taken up by the tumor. The major site of off-target uptake was the kidneys and to some extent the liver. (Z(HER2:2891)) 2-ABD-MC-DM1 was found to have a half-life in circulation of 14 h. The compound was tolerated well by mice at 8.5 mg/kg and was shown to extend survival of mice bearing HER2 over-expressing tumors. The findings in this study show that affibody molecules are a promising class of engineered affinity proteins to specifically deliver small molecular drugs to cancer cells and that such conjugates are potential candidates for clinical evaluation on HER2-overexpressing cancers.

  • 2.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Perols, Anna
    Tsourma, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Robillard, Marc
    Rossin, Raffaella
    Ten Hoeve, Wolter
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson Karlström, Amelie
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Feasibility of affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting2016In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 3, p. 431-436Article in journal (Refereed)
    Abstract [en]

    Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal re-absorption of affibody molecules prevents the use of residualizing radiometals, including a number of promising low energy beta- and alpha-emitters, for radionuclide therapy. We tested a hypothesis that affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys.

    Methods:

    TCO was conjugated to the anti-HER2 affibody molecule Z2395. DOTA-tetrazine was labeled with indium-111 and lutetium-177. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts.

    Results:

    125I-Z2395-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45±16 pM. 111In-tetrazine bound specifically and selectively to Z2395-TCO pre-treated cells. In vivo studies demonstrated HER2-specific 125I-Z2395-TCO accumulation in xenografts. TCO-mediated 111In-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z2395-TCO. At 1 h post injection, the tumor uptake of 111In-tetrazine and 177Lu-tetrazine was ca. 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of 111In in comparison with direct targeting.

    Conclusion:

    The feasibility of affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pretargeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.

  • 3.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Tsourma, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Preclin PET Platform, Uppsala, Sweden..
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Perols, A.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Robillard, M.
    Tagworks Pharmaceut, Eindhoven, Netherlands..
    Rossin, R.
    Tagworks Pharmaceut, Eindhoven, Netherlands..
    ten Hoeve, W.
    Syncom BV, Groningen, Netherlands..
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Karlstrom, A. Eriksson
    KTH, Div Prot Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting: proof-of-principle2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, no S1, p. S246-S246Article in journal (Other academic)
  • 4.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Westerlund, Kristina
    KTH Royal Inst Technol, Div Prot Technol, Sch Biotechnol, Stockholm, Sweden..
    Velletta, Justin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Eriksson Karlström, Amelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Evaluation of affibody molecule-based PNA-mediated radionuclide pretargeting: Development of an optimized conjugation protocol and 177Lu labeling2017In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 54, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Introduction: We have previously developed a pretargeting approach for affibody-mediated cancer therapy based on PNA-PNA hybridization. In this article we have further developed this approach by optimizing the production of the primary agent, Z(HER2.342)-SR-HP1, and labeling the secondary agent, HP2, with the therapeutic radionuclide Lu-177. We also studied the biodistribution profile of Lu-177-HP2 in mice, and evaluated pretargeting with Lu-177-HP2 in vitro and in vivo.

    Methods: The biodistribution profile of Lu-177-HP2 was evaluated in NMRI mice and compared to the previously studied In-111-HP2. Pretargeting using Lu-177-HP2 was studied in vitro using the HER2-expressing cell lines BT-474 and SKOV-3, and in vivo in mice bearing SKOV-3 xenografts.

    Results and conclusion: Using an optimized production protocol for Z(HER2:342)-SR-HP1 the ligation time was reduced from 15 h to 30 min, and the yield increased from 45% to 70%. Lu-177-labeled HP2 binds specifically in vitro to BT474 and SKOV-3 cells pre-treated with Z(HER2:342)-SR-HP1.Lu-177-HP2 was shown to have a more rapid blood clearance compared to In-111-HP2 in NMRI mice, and the measured radioactivity in blood was 0.22 +/- 0.1 and 0.68 +/- 0.07%ID/g for Lu-177- and In-111-HP2, respectively, at 1 h p.i. In contrast, no significant difference in kidney uptake was observed (4.47 +/- 1.17 and 3.94 +/- 0.58%ID/g for Lu-177- and In-111-HP2, respectively, at I h p.i.). Co-injection with either Gelofusine or lysine significantly reduced the kidney uptake for Lu-177-HP2 (1.0 +/- 0.1 and 1.6 +/- 0.2, respectively, vs. 2.97 +/- 0.87%ID/g in controls at 4 h p.i.). Lu-177-HP2 accumulated in SKOV-3 xenografts in BALB/C nu/nu mice when administered after injection of Z(HER2:342)-SR-HP1. Without pre-injection of Z(HER2:342)-SR-HP1, the uptake of Lu-177-HP2 was about 90-fold lower in tumor (0.23 +/- 0.08 vs. 20.7 +/- 3.5%ID/g). The tumor-to-kidney radioactivity accumulation ratio was almost 5-fold higher in the group of mice pre-injected with Z(HER2:342)-SR-HP1. In conclusion, (177)LuHP2 was shown to be a promising secondary agent for affibody-mediated tumor pretargeting in vivo.

  • 5.
    Andersson, Ken G.
    et al.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Oroujeni, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Ståhl, Stefan
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Feasibility of imaging of epidermal growth factor receptor expression with ZEGFR: 2377 affibody molecule labeled with 99mTc using a peptide-based cysteine-containing chelator2016In: International journal of oncology, ISSN 1791-2423, Vol. 49, no 6, p. 2285-2293Article in journal (Refereed)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is overexpressed in a number of malignant tumors and is a molecular target for several specific anticancer antibodies and tyrosine kinase inhibitors. The overexpression of EGFR is a predictive biomarker for response to several therapy regimens. Radionuclide molecular imaging might enable detection of EGFR overexpression by a non-invasive procedure and could be used repeatedly. Affibody molecules are engineered scaffold proteins, which could be selected to have a high affinity and selectivity to predetermined targets. The anti-EGFR ZEGFR:2377 affibody molecule is a potential imaging probe for EGFR detection. The use of the generator-produced radionuclide 99mTc should facilitate clinical translation of an imaging probe due to its low price, availability and favorable dosimetry of the radionuclide. In the present study, we evaluated feasibility of ZEGFR:2377 labeling with 99mTc using a peptide-based cysteine-containing chelator expressed at the C-terminus of ZEGFR:2377. The label was stable in vitro under cysteine challenge. In addition, 99mTc-ZEGFR:2377 was capable of specific binding to EGFR-expressing cells with high affinity (274 pM). Studies in BALB/C nu/nu mice bearing A431 xenografts demonstrated that 99mTc-ZEGFR:2377 accumulates in tumors in an EGFR-specific manner. The tumor uptake values were 3.6±1 and 2.5±0.4% ID/g at 3 and 24 h after injection, respectively. The corresponding tumor-to-blood ratios were 1.8±0.4 and 8±3. The xenografts were clearly visualized at both time-points. This study demonstrated the potential of 99mTc-labeled ZEGFR:2377 for imaging of EGFR in vivo.

  • 6.
    Bass, Tarek Z.
    et al.
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Affibody AB, SE-17163 Solna, Sweden.
    Löfblom, John
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ståhl, Stefan
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    In vivo evaluation of a novel format of a bivalent HER3-targeting and albumin- binding therapeutic affibody construct2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43118Article in journal (Refereed)
    Abstract [en]

    Overexpression of human epidermal growth factor receptor 3 (HER3) is involved in resistance to several therapies for malignant tumours. Currently, several anti-HER3 monoclonal antibodies are under clinical development. We introduce an alternative approach to HER3-targeted therapy based on engineered scaffold proteins, i.e. affibody molecules. We designed a small construct (22.5 kDa, denoted 3A3), consisting of two high-affinity anti-HER3 affibody molecules flanking an albumin-binding domain ABD, which was introduced for prolonged residence in circulation. In vitro, 3A3 efficiently inhibited growth of HER3-expressing BxPC-3 cells. Biodistribution in mice was measured using 3A3 that was site-specifically labelled with In-111 via a DOTA chelator. The residence time of In-111-DOTA-3A3 in blood was extended when compared with the monomeric affibody molecule. In-111-DOTA-3A3 accumulated specifically in HER3-expressing BxPC-3 xenografts in mice. However, In-111-DOTA-3A3 cleared more rapidly from blood than a size-matched control construct In-111-DOTA-TAT, most likely due to sequestering of 3A3 by mErbB3, the murine counterpart of HER3. Repeated dosing and increase of injected protein dose decreased uptake of In-111-DOTA-3A3 in mErbB3-expressing tissues. Encouragingly, growth of BxPC-3 xenografts in mice was delayed in an experimental (pilot-scale) therapy study using 3A3. We conclude that the 3A3 affibody format seems promising for treatment of HER3-overexpressing tumours.

  • 7.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Andersson, Ken G.
    KTH Royal Inst Technol, Dept Prot Technol.
    Dam, Johan H.
    Odense Univ Hosp, Dept Nucl Med.
    Olsen, Birgitte B.
    Odense Univ Hosp, Dept Nucl Med..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ståhl, Stefan
    KTH Royal Inst Technol, Dept Prot Technol.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Technol.
    Thisgaard, Helge
    Odense Univ Hosp, Dept Nucl Med.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 5961Article in journal (Refereed)
    Abstract [en]

    Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The In-111-labelled DOTA-conjugated Z(EGFR:2377) Affibody molecule was successfully used for imaging of EGFR-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-Z(EGFR:2377). DOTA-Z(EGFR:2377) was labelled with Co-57 (T-1/2 = 271.8 d), Co-55 (T-1/2 = 17.5 h), and, for comparison, with the positron-emitting radionuclide Ga-68 (T-1/2 = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope Co-57 was used in animal studies. Both Co-57-DOTA-Z(EGFR:2377) and Ga-68-DOTA-Z(EGFR:2377) demonstrated EGFR-specific accumulation in A431 xenografts and EGFR-expressing tissues in mice. Tumour-to-organ ratios for the radiocobalt-labelled DOTA-Z(EGFR:2377) were significantly higher than for the gallium-labelled counterpart already at 3 h after injection. Importantly, Co-57-DOTA-Z(EGFR:2377) demonstrated a tumour-to-liver ratio of 3, which is 7-fold higher than the tumour-to-liver ratio for (68)GaDOTA-Z(EGFR:2377). The results of this study suggest that the positron-emitting cobalt isotope 55Co would be an optimal label for DOTA-Z(EGFR:2377) and further development should concentrate on this radionuclide as a label.

  • 8.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Andersson, Ken G
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Pichl, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ståhl, Stefan
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    PET imaging of epidermal growth factor receptor expression in tumours using 89Zr-labelled ZEGFR: 2377 affibody molecules.2016In: International journal of oncology, ISSN 1791-2423, Vol. 48, no 4, p. 1325-1332Article in journal (Refereed)
    Abstract [en]

    Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which is overexpressed in many types of cancer. The use of EGFR-targeting monoclonal antibodies and tyrosine-kinase inhibitors improves significantly survival of patients with colorectal, non-small cell lung cancer and head and neck squamous cell carcinoma. Detection of EGFR overexpression provides important prognostic and predictive information influencing management of the patients. The use of radionuclide molecular imaging would enable non-invasive repeatable determination of EGFR expression in disseminated cancer. Moreover, positron emission tomography (PET) would provide superior sensitivity and quantitation accuracy in EGFR expression imaging. Affibody molecules are a new type of imaging probes, providing high contrast in molecular imaging. In the present study, an EGFR-binding affibody molecule (ZEGFR:2377) was site-specifically conjugated with a deferoxamine (DFO) chelator and labelled under mild conditions (room temperature and neutral pH) with a positron-emitting radionuclide 89Zr. The 89Zr-DFO-ZEGFR:2377 tracer demonstrated specific high affinity (160±60 pM) binding to EGFR-expressing A431 epidermoid carcinoma cell line. In mice bearing A431 xenografts, 89Zr-DFO-ZEGFR:2377 demonstrated specific uptake in tumours and EGFR-expressing tissues. The tracer provided tumour uptake of 2.6±0.5% ID/g and tumour-to-blood ratio of 3.7±0.6 at 24 h after injection. 89Zr-DFO-ZEGFR:2377 provides higher tumour-to-organ ratios than anti-EGFR antibody 89Zr-DFO-cetuximab at 48 h after injection. EGFR‑expressing tumours were clearly visualized by microPET using 89Zr-DFO-ZEGFR:2377 at both 3 and 24 h after injection. In conclusion, 89Zr-DFO-ZEGFR:2377 is a potential probe for PET imaging of EGFR-expression in vivo.

  • 9.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Andersson, K.
    KTH Royal Inst Technol, Stockholm, Sweden..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala Univ, Uppsala, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Evaluation of Affibody Molecules for Radionuclide Imaging of Carbonic Abhydrase IX Expression In Vivo2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S428-S428Article in journal (Refereed)
  • 10.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Andersson, Ken G.
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Ridgeview Instruments AB, SE-74020 Vange, Sweden.
    Löfblom, John
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Affibody AB, SE-17163 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Comparative evaluation of Affibody molecules for radionuclide imaging of in vivo expression of carbonic anhydrase IX2016In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 11, p. 3676-3687Article in journal (Refereed)
    Abstract [en]

    Overexpression of the enzyme carbonic anhydrase IX (CAIX) is documented for chronically hypoxic malignant tumors as well as for normoxic renal cell carcinoma. Radionuclide molecular imaging of CAIX would be useful for detection of hypoxic areas in malignant tumors, for patients' stratification of CAIX-targeted therapies and for discrimination of primary malignant and benign renal tumors. Earlier, we have reported feasibility of in vivo radionuclide based imaging of CAIX expressing tumors using Affibody molecules, small affinity proteins based on a non-immunoglobulin scaffold. In this study, we compared imaging properties of several anti-CAIX Affibody molecules having identical scaffold parts and competing for the same epitope on CAIX, but having different binding paratopes. Four variants were labeled using residualizing 99mTc and non-residualizing 125I labels. All radiolabeled variants demonstrated high-affinity detection of CAIX-expressing cell line SK-RC-52 in vitro and specific accumulation in SK-RC-52 xenografts in vivo. 125I-labeled conjugates demonstrated much lower radioactivity uptake in kidneys but higher radioactivity concentration in blood compared with 99mTc-labed counterparts. Although all variants cleared rapidly from blood and non-specific compartments, there was noticeably difference in their biodistribution. The best variant for imaging of expression of CAIX- in disseminated cancer was 99mTc-(HE)3-ZCAIX:2 providing tumor uptake of 16.3±0.9 %ID/g and tumor-to-blood ratio of 44±7 at 4 h after injection. For primary renal cell carcinoma, the most promising imaging candidate was 125I-ZCAIX:4 providing tumor-kidney ratio of 2.1±0.5. In conclusion, several clones of scaffold proteins should be evaluated to select the best variant for development of an imaging probe with optimal sensitivity for the intended application.

  • 11.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lindbo, S.
    KTH Royal Inst Technol, Dept Prot Technol, Stockholm, Sweden..
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Velletta, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Hober, S.
    KTH Royal Inst Technol, Dept Prot Technol, Stockholm, Sweden..
    Influence of the N-terminal amino acid sequence on imaging properties of In-111-labeled anti-HER2 scaffold protein ADAPT62016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S55-S55Article in journal (Refereed)
  • 12.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lindbo, S.
    Royal Inst Technol, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Oroujeni, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Hober, S.
    Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Selection of the most optimal ADAPT6-based probe for imaging of HER2 using PET and SPECT2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S77-S78Article in journal (Other academic)
  • 13.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lindbo, Sarah
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    Borin, Jesper
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    von Witting, Emma
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Oroujeni, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    Comparative evaluation of dimeric and monomeric forms of ADAPT scaffold protein for targeting of HER2-expressing tumours2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 134, p. 37-48Article in journal (Refereed)
    Abstract [en]

    ADAPTs are small engineered non-immunoglobulin scaffold proteins, which have demonstrated very promising features as vectors for radionuclide tumour targeting. Radionuclide imaging of human epidermal growth factor 2 (HER2) expression in vivo might be used for stratification of patients for HER2-targeting therapies. ADAPT6, which specifically binds to HER2, has earlier been shown to have very promising features for in vivo targeting of HER2 expressing tumours. In this study we tested the hypothesis that dimerization of ADAPT6 would increase the apparent affinity to HER2 and accordingly improve tumour targeting. To find an optimal molecular design of dimers, a series of ADAPT dimers with different linkers, -SSSG- (DiADAPT6L1), -(SSSG)(2)- (DiADAPT6L2), and -(SSSG)(3)- (DiADAPT6L3) was evaluated. Dimers in combination with optimal linker lengths demonstrated increased apparent affinity to HER2. The best variants, DiADAPT6L2 and DiADAPT6L3 were site-specifically labelled with In-111 and I-125, and compared with a monomeric ADAPT6 in mice bearing HER2-expressing tumours. Despite higher affinity, both dimers had lower tumour uptake and lower tumour-to-organ ratios compared to the monomer. We conclude that improved affinity of a dimeric form of ADAPT does not compensate the disadvantage of increased size. Therefore, increase of affinity should be obtained by affinity maturation and not by dimerization.

  • 14.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lindbo, Sarah
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Velletta, Justin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Bogdan, Mitran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Hober, Sophia
    Influence of the N-Terminal Composition on Targeting Properties of Radiometal-Labeled Anti-HER2 Scaffold Protein ADAPT62016In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 27, no 11, p. 2678-2688Article in journal (Refereed)
    Abstract [en]

    Radionuclide-imaging-based stratification of patients to targeted therapies makes cancer treatment more personalized and therefore more efficient. Albumin-binding domain derived affinity proteins (ADAPTs) constitute a novel group of imaging probes based on the scaffold of an albumin-binding domain (ABD). To evaluate how different compositions of the N-terminal sequence of ADAPTs influence their biodistribution, a series of human epidermal growth factor receptor type 2 (HER2)-binding ADAPT6 derivatives with different N-terminal sequences were created: GCH6DANS (2), GC(HE)3DANS (3), GCDEAVDANS (4), and GCVDANS(5). These were compared with the parental variant: GCSS(HE)3DEAVDANS (1). All variants were site-specifically conjugated with a maleimido-derivative of a DOTA chelator and labeled with (111)In. Binding to HER2-expressing cells in vitro, in vivo biodistribution as well as targeting properties of the new variants were compared with properties of the (111)In-labeled parental ADAPT variant 1 ((111)In-DOTA-1). The composition of the N-terminal sequence had an apparent influence on biodistribution of ADAPT6 in mice. The use of a hexahistidine tag in (111)In-DOTA-2 was associated with elevated hepatic uptake compared to the (HE)3-containing counterpart, (111)In-DOTA-3. All new variants without a hexahistidine tag demonstrated lower uptake in blood, lung, spleen, and muscle compared to uptake in the parental variant. The best new variants, (111)In-DOTA-3 and (111)In-DOTA-5, provided tumor uptakes of 14.6 ± 2.4 and 12.5 ± 1.3% ID/g at 4 h after injection, respectively. The tumor uptake of (111)In-DOTA-3 was significantly higher than the uptake of the parental (111)In-DOTA-1 (9.1 ± 2.0% ID/g). The tumor-to-blood ratios of 395 ± 75 and 419 ± 91 at 4 h after injection were obtained for (111)In-DOTA-5 and (111)In-DOTA-3, respectively. In conclusion, the N-terminal sequence composition affects the biodistribution and targeting properties of ADAPT-based imaging probes, and its optimization may improve imaging contrast.

  • 15.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lindbo, Sarah
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, Stockholm, Sweden..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Hober, Sophia
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, Stockholm, Sweden..
    Comparative evaluation of tumor targeting using the anti-HER2 ADAPT scaffold protein labeled at the C-terminus with indium-111 or technetium-99m2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 14780Article in journal (Refereed)
    Abstract [en]

    ABD-Derived Affinity Proteins (ADAPTs) is a novel class of engineered scaffold proteins derived from an albumin-binding domain of protein G. The use of ADAPT6 derivatives as targeting moiety have provided excellent preclinical radionuclide imaging of human epidermal growth factor 2 (HER2) tumor xenografts. Previous studies have demonstrated that selection of nuclide and chelator for its conjugation has an appreciable effect on imaging properties of scaffold proteins. In this study we performed a comparative evaluation of the anti-HER2 ADAPT having an aspartate-glutamate-alanine-valine-aspartate-alanine-asparagine-serine (DEAVDANS) N-terminal sequence and labeled at C-terminus with (99)mTc using a cysteine-containing peptide based chelator, glycine-serine-serine-cysteine (GSSC), and a similar variant labeled with In-111 using a maleimido derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. Both (99)mTc-DEAVDANS-ADAPT6-GSSC and In-111-DEAVDANS-ADAPT6-GSSC-DOTA accumulated specifically in HER2-expressing SKOV3 xenografts. The tumor uptake of both variants did not differ significantly and average values were in the range of 19-21% ID/g. However, there was an appreciable variation in uptake of conjugates in normal tissues that resulted in a notable difference in the tumor-to-organ ratios. The In-111-DOTA label provided 2-6 fold higher tumor-to-organ ratios than (99)mTc-GSSC and is therefore the preferable label for ADAPTs.

  • 16.
    Lindbo, Sarah
    et al.
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Hober, Sofia
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Radionuclide tumor targeting using ADAPT scaffold proteins: aspects of label positioning and residualizing properties of the label2018In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, no 1, p. 93-99Article in journal (Refereed)
    Abstract [en]

    Visualization of cancer-associated alterations of molecular phenotype using radionuclide imaging is a noninvasive approach to stratifying patients for targeted therapies. The engineered albumin-binding domain-derived affinity protein (ADAPT) is a promising tracer for radionuclide molecular imaging because of its small size (6.5 kDa), which satisfies the precondition for efficient tumor penetration and rapid clearance. Previous studies demonstrated that the human epidermal growth factor receptor type 2 (HER2)-targeting ADAPT6 labeled with radiometals at the N terminus is able to image HER2 expression in xenografts a few hours after injection. The aim of this study was to evaluate whether the use of a non-residualizing label or placement of the labels at the C terminus would further improve the targeting properties of ADAPT6. Methods: Two constructs, Cys(2)-ADAPT6 and Cys(59)-ADAPT6, having the (HE)(3)DANS sequence at the N terminus were produced and site-specifically labeled using In-111-DOTA or I-125-iodo-((4-hydroxyphenyl) ethyl) maleimide (HPEM). The conjugates were compared in vitro and in vivo. HER2-targeting properties and biodistribution were evaluated in BALB/C nu/nu mice bearing ovarian carcinoma cell (SKOV-3) xenografts. Results: Specific HER2 binding and high affinity were preserved after labeling. Both Cys(2)-ADAPT6 and Cys59-ADAPT6 were internalized slowly by HER2-expressing cancer cells. Depending on the label position, uptake at 4 h after injection varied from 10% to 22% of the injected dose per gram of tumor tissue. Regardless of terminus position, the I-125-HPEM label provided more than 140-fold lower renal uptake than the In-111-DOTA label at 4 after injection. The tumor-to-organ ratios were, in contrast, higher for both of the (111)InDOTA- labeled ADAPT variants in other organs. Tumor-to-blood ratios for In-111-labeled Cys(2)-ADAPT6 and Cys(59)-ADAPT6 did not differ significantly (250-280), but In-111-DOTA-Cys(59)-ADAPT6 provided significantly higher tumor-to-lung, tumor-to-liver, tumor-to-spleen, and tumor-to-muscle ratios. Radioiodinated variants had similar tumor-to-organ ratios, but I-125-HPEM-Cys(59)-ADAPT6 had significantly higher tumor uptake and a higher tumor-to-kidney ratio. Conclusion: Residualizing properties of the label strongly influence the targeting properties of ADAPT6. The position of the radiolabel influences targeting as well, although to a lesser extent. Placement of a label at the C terminus yields the best biodistribution features for both radiometal and radiohalogen labels. Low renal retention of the radioiodine label creates a precondition for radionuclide therapy using I-131-labeled HPEM-Cys(59)-ADAPT6.

  • 17.
    Lindbo, Sarah
    et al.
    School of Engineering in Chemistry, Biotechnology and Health (CBH), Division of Protein Science, KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Oroujeni, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Hober, Sophia
    School of Engineering in Chemistry, Biotechnology and Health (CBH), Division of Protein Science, KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Optimized Molecular Design of ADAPT-Based HER2-Imaging Probes Labeled with 111In and 68Ga2018In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 7, p. 2674-2683Article in journal (Refereed)
    Abstract [en]

    Radionuclide molecular imaging is a promising tool for visualization of cancer associated molecular abnormalities in vivo and stratification of patients for specific therapies. ADAPT is a new type of small engineered proteins based on the scaffold of an albumin binding domain of protein G. ADAPTs have been utilized to select and develop high affinity binders to different proteinaceous targets. ADAPT6 binds to human epidermal growth factor 2 (HER2) with low nanomolar affinity and can be used for its in vivo visualization. Molecular design of 111In-labeled anti-HER2 ADAPT has been optimized in several earlier studies. In this study, we made a direct comparison of two of the most promising variants, having either a DEAVDANS or a (HE)3DANS sequence at the N-terminus, conjugated with a maleimido derivative of DOTA to a GSSC amino acids sequence at the C-terminus. The variants (designated DOTA-C59-DEAVDANS-ADAPT6-GSSC and DOTA-C61-(HE)3DANS-ADAPT6-GSSC) were stably labeled with 111In for SPECT and 68Ga for PET. Biodistribution of labeled ADAPT variants was evaluated in nude mice bearing human tumor xenografts with different levels of HER2 expression. Both variants enabled clear discrimination between tumors with high and low levels of HER2 expression. 111In-labeled ADAPT6 derivatives provided higher tumor-to-organ ratios compared to 68Ga-labeled counterparts. The best performing variant was DOTA-C61-(HE)3DANS-ADAPT6-GSSC, which provided tumor-to-blood ratios of 208 ± 36 and 109 ± 17 at 3 h for 111In and 68Ga labels, respectively.

  • 18.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Altai, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Hofstrom, C.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Graslund, T.
    Evaluation of 99mTc-ZIGF1R:4551-GGGC Affibody Molecule, a New Construct for Imaging the Insulin-like Growth Factor Type 1 Receptor Expression2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S440-S440, article id P288Article in journal (Other academic)
  • 19.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Andersson, Ken Gosta
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Lindström, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Stahl, Stefan
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löfblom, John
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Affibody-mediated imaging of EGFR expression in prostate cancer using radiocobalt-labeled DOTA-Z(EGFR:2377)2019In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 41, no 1, p. 534-542Article in journal (Refereed)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is often overexpressed during prostate cancer (PCa) progression towards androgen-independence after hormone therapy, but the overexpression is lower than in other types of cancers. Despite the low expression, EGFR has emerged as a promising therapeutic target for patients with castration-resistant PCa. Non-invasive methods for determination of EGFR expression in PCa can serve for patient stratification and therapy response monitoring. Radionuclide imaging probes based on affibody molecules (7 kDa) provide high contrast imaging of cancer-associated molecular targets. We hypothesized that the anti-EGFR affibody molecule DOTA-Z(EGFR:2377) labeled with Co-55 (positron-emitter, T1/2=17.5 h) would enable imaging of EGFR expression in PCa xenografts. The human PCa cell line DU-145 was used for in vitro and in vivo experiments and Co-57 was used as a surrogate for Co-55 in the present study. Binding of Co-57-DOTA-Z(EGFR:2377) to EGFR-expressing xenografts was saturable with anti-EGFR monoclonal antibody cetuximab, which would motivate the use of this tracer for monitoring the receptor occupancy during treatment. A significant dose-dependent difference in radioactivity accumulation in tumors and normal organs was observed when the biodistribution was studied 3 h after the injection of 10 and 35 mu g of Co-57-DOTA-Z(EGFR:2377): At lower doses the tumor uptake was 2-fold higher although tumor-to-organ ratios were not altered. For clinically relevant organs for PCa, tumor-to-organ ratios increased with time, and at 24 h pi were 2.2 +/- 0.5 for colon, 7 +/- 2 for muscle, and 4.0 +/- 0.7 for bones. Small animal SPECT/CT images confirmed the capacity of radiocobalt labeled DOTA-Z(EGFR:2377) to visualize EGFR expression in PCa. In conclusion, the present study demonstrated the feasibility of using the radiocobalt labeled anti-EGFR affibody conjugate Z(EGFR:2377) as an imaging agent for in vivo visualization of low EGFR-expressing tumors, like PCa, and for monitoring of receptor occupancy during cetuximab therapy as well as the importance of optimal dosing in order to achieve higher sensitivity molecular imaging.

  • 20.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Guler, R.
    KTH Royal Inst Technol, Stockholm, Sweden..
    Lindström, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Fleetwood, F.
    KTH Royal Inst Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ståhl, S.
    KTH Royal Inst Technol, Stockholm, Sweden..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden..
    Feasibility of in vivo imaging of VEGFR2 expression using high affinity antagonistic biparatopic affibody construct Z(VEGFR2)-Bp(2)2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S97-S98Article in journal (Refereed)
  • 21.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Güler, Rezan
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.
    Roche, Francis P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lindström, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Fleetwood, Filippa
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ståhl, Stefan
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.
    Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model2018In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 8, no 16, p. 4462-4476Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor receptor-2 (VEGFR2) is a key mediator of angiogenesis and therefore a promising therapeutic target in malignancies including glioblastoma multiforme (GBM). Molecular imaging of VEGFR2 expression may enable patient stratification for antiangiogenic therapy. The goal of the current study was to evaluate the capacity of the novel anti-VEGFR2 biparatopic affibody conjugate (Z(VEGFR2)-Bp(2)) for in vivo visualization of VEGFR2 expression in GBM.

    Methods: Z(VEGFR2)-Bp(2) coupled to a NODAGA chelator was generated and radiolabeled with indium-111. The VEGFR2-expressing murine endothelial cell line MS1 was used to evaluate in vitro binding specificity and affinity, cellular processing and targeting specificity in mice. Further tumor targeting was studied in vivo in GL261 glioblastoma orthotopic tumors. Experimental imaging was performed.

    Results: [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) bound specifically to VEGFR2 (K-D=33 +/- 18 pM). VEGFR2-mediated accumulation was observed in liver, spleen and lungs. The tumor-to-organ ratios 2 h post injection for mice bearing MS1 tumors were approximately 11 for blood, 15 for muscles and 78 for brain. Intracranial GL261 glioblastoma was visualized using SPECT/CT. The activity uptake in tumors was significantly higher than in normal brain tissue. The tumor-to-cerebellum ratios after injection of 4 mu g [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) were significantly higher than the ratios observed for the 40 mu g injected dose and for the non-VEGFR2 binding size-matched conjugate, demonstrating target specificity. Microautoradiography of cryosectioned CNS tissue was in good agreement with the SPECT/CT images.

    Conclusion: The anti-VEGFR2 affibody conjugate [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) specifically targeted VEGFR2 in vivo and visualized its expression in a murine GBM orthotopic model. Tumor-to-blood ratios for [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) were higher compared to other VEGFR2 imaging probes. [In-111]In-NODAGA-Z(VEGFR2)-Bp(2) appears to be a promising probe for in vivo noninvasive visualization of tumor angiogenesis in glioblastoma.

  • 22.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Azamy, F.
    Uppsala University.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Konijnenberg, M.
    Erasmus MC, Rotterdam, Netherlands.
    Maina-Nock, T.
    NCSR Demokritos, Athens, Greece.
    Nock, B. A.
    NCSR Demokritos, Athens, Greece.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala Univ, Uppsala, Sweden.
    GRPR-targeted radiotherapy using the Lu-177-labeled GRPR-antagonist DOTAGA-PEG(2)-RM262018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S29-S30Article in journal (Other academic)
  • 23.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Thisgaard, H.
    Ctr Single Particle Sci & Engn, Odense, Denmark.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Azamy, F.
    Uppsala University.
    Dam, J.
    Odense Univ Hosp, Odense, Denmark.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Selection of optimal macrocyclic chelator for high contrast PET imaging of gastrin releasing peptide receptor using cobalt-labeled bombesin antagonist RM262018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S672-S673Article in journal (Other academic)
  • 24.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Thisgaard, Helge
    Odense University Hospital, PET & Cyclotron Unit, Department of Nuclear Medicine; University of Southern Denmark, Department of Clinical Research.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Dam, Johan Hygum
    Odense University Hospital, PET & Cyclotron Unit, Department of Nuclear Medicine.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    High Contrast PET Imaging of GRPR Expression in Prostate Cancer Using Cobalt-Labeled Bombesin Antagonist RM262017In: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, article id UNSP 6873684Article in journal (Refereed)
    Abstract [en]

    High gastrin releasing peptide receptor (GRPR) expression is associated with numerous cancers including prostate and breast cancer. The aim of the current study was to develop a Co-55-labeled PET agent based on GRPR antagonist RM26 for visualization of GRPR-expressing tumors. Labeling with Co-57 and Co-55, stability, binding specificity, and in vitro and in vivo characteristics of Co-57-NOTA-PEG(2)-RM26 were studied. NOTA-PEG(2)-RM26 was successfully radiolabeled with Co-57 and Co-55 with high yields and demonstrated high stability. The radiopeptide showed retained binding specificity to GRPR in vitro and in vivo. Co-57-NOTA-PEG(2)-RM26 biodistribution in mice was characterized by rapid clearance of radioactivity from blood and normal non-GRPR-expressing organs and low hepatic uptake. The clearance was predominantly renal with a low degree of radioactivity reabsorption. Tumor-to-blood ratios were approximately 200 (3 h pi) and 1000 (24 h pi). The favorable biodistribution of cobalt-labeled NOTA-PEG(2)-RM26 translated into high contrast preclinical PET/CT (using Co-55) and SPECT/CT (using Co-57) images of PC-3 xenografts. The initial biological results suggest that Co-55-NOTA-PEG(2)-RM26 is a promising tracer for PET visualization of GRPR-expressing tumors.

  • 25.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Development of radiocobalt-labeled GRPR antagonist NOTA-PEG2-RM26.2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, no S1, p. S142-S142Article in journal (Other academic)
  • 26.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Influence of chelators on biodistribution and targeting properties of GRPR antagonist2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S320-S320, article id PW012Article in journal (Other academic)
  • 27.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Selection of optimal chelator improves the contrast of GRPR imaging using bombesin analogue RM26.2016In: International journal of oncology, ISSN 1791-2423, Vol. 48, no 5, p. 2124-2134Article in journal (Refereed)
    Abstract [en]

    Bombesin (BN) analogs bind with high affinity to gastrin-releasing peptide receptors (GRPRs) that are up-regulated in prostate cancer and can be used for the visualization of prostate cancer. The aim of this study was to investigate the influence of radionuclide-chelator complexes on the biodistribution pattern of the 111In-labeled bombesin antagonist PEG2-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (PEG2-RM26) and to identify an optimal construct for SPECT imaging. A series of RM26 analogs N-terminally conjugated with NOTA, NODAGA, DOTA and DOTAGA via a PEG2 spacer were radiolabeled with 111In and evaluated both in vitro and in vivo. The conjugates were successfully labeled with 111In with 100% purity and retained binding specificity to GRPR and high stability. The cellular processing of all compounds was characterized by slow internalization. The IC50 values were in the low nanomolar range, with lower IC50 values for positively charged natIn-NOTA-PEG2-RM26 (2.6±0.1 nM) and higher values for negatively charged natIn-DOTAGA-PEG2-RM26 (4.8±0.5 nM). The kinetic binding studies showed KD values in the picomolar range that followed the same pattern as the IC50 data. The biodistribution of all compounds was studied in BALB/c nu/nu mice bearing PC-3 prostate cancer xenografts. Tumor targeting and biodistribution studies displayed rapid clearance of radioactivity from the blood and normal organs via kidney excretion. All conjugates showed similar uptake in tumors at 4 h p.i. The radioactivity accumulation in GRPR-expressing organs was significantly lower for DOTA- and DOTAGA-containing constructs compared to those containing NOTA and NODAGA. 111In-NOTA-PEG2-RM26 with a positively charged complex showed the highest initial uptake and the slowest clearance of radioactivity from the liver. At 4 h p.i., DOTA- and DOTAGA-coupled analogs showed significantly higher tumor-to-organ ratios compared to NOTA- and NODAGA-containing variants. The NODAGA conjugate demonstrated the best retention of radioactivity in tumors, and, at 24 h p.i., had the highest contrast to blood, muscle and bones.

  • 28.
    Orlova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Maina, T.
    INRASTES NCSR Demokritos, Athens, Greece.
    Nock, B. A.
    INRASTES NCSR Demokritos, Athens, Greece.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    GRPR-Targeted Radiotherapy: Influence of Chelator on Labeling and Biodistribution of Four Lu-177-Labeled Analogues of the GRPR-Antagonist PEG2-RM262017In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, p. S295-S296Article in journal (Other academic)
  • 29.
    Orlova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Bass, T.
    Royal Inst Technol, Stockholm, Sweden..
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, J.
    Royal Inst Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ståhl, S.
    Royal Inst Technol, Stockholm, Sweden..
    In vivo evaluation of pharmacokinetics, tumors targeting and therapeutic efficacy of a novel format of HER3-targeting affibody molecule with prolonged blood circulation2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S237-S237Article in journal (Refereed)
  • 30.
    Orlova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Andersson, K. G.
    Royal Inst Technol, Stockholm, Sweden.
    Löfblom, J.
    Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Imaging contrast of HER3 expression using monomeric affibody-based imaging probe can be improved by co-injection of affibody trimer2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no Supplement 1, p. S673-S673Article in journal (Other academic)
  • 31.
    Orlova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Influence of chelators on targeting properties of In-111 and Ga-68 labeled GRPR antagonist2015In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, p. S88-S88Article in journal (Other academic)
  • 32.
    Oroujeni, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Anderson, K. G.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Steinhardt, X.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Ståhl, S.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Influence of composition of cysteine-containing peptide based chelators on biodistribution of Tc-99m-labelled anti-EGFR affibody molecules2017In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, p. S347-S348Article in journal (Other academic)
  • 33.
    Oroujeni, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Andersson, K.
    KTH Royal Inst Technol, Stockholm, Sweden..
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Imaging of EGFR Expression Using 99mTC-Labelled ZEGFR:2377 Affibody Molecule2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S238-S238Article in journal (Refereed)
  • 34.
    Oroujeni, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Andersson, Ken G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Steinhardt, Xenia
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden..
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden..
    Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules2018In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 50, no 8, p. 981-994Article in journal (Refereed)
    Abstract [en]

    Epidermal growth factor receptor (EGFR) is overexpressed in a number of cancers and is the molecular target for several anti-cancer therapeutics. Radionuclide molecular imaging of EGFR expression should enable personalization of anti-cancer treatment. Affibody molecule is a promising type of high-affinity imaging probes based on a non-immunoglobulin scaffold. A series of derivatives of the anti-EGFR affibody molecule ZEGFR:2377, having peptide-based cysteine-containing chelators for conjugation of Tc-99m, was designed and evaluated. It was found that glutamate-containing chelators Gly-Gly-Glu-Cys (GGEC), Gly-Glu-Glu-Cys (GEEC) and Glu-Glu-Glu-Cys (EEEC) provide the best labeling stability. The glutamate containing conjugates bound to EGFR-expressing cells specifically and with high affinity. Specific targeting of EGFR-expressing xenografts in mice was demonstrated. The number of glutamate residues in the chelator had strong influence on biodistribution of radiolabeled affibody molecules. Increase of glutamate content was associated with lower uptake in normal tissues. The Tc-99m-labeled variant containing the EEEC chelator provided the highest tumor-to-organ ratios. In conclusion, optimizing the composition of peptide-based chelators enhances contrast of imaging of EGFR-expression using affibody molecules.

  • 35.
    Oroujeni, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Andersson, K.
    Royal Inst Technol, Stockholm, Sweden.
    Löfblom, J.
    Royal Inst Technol, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala Univ, Uppsala, Sweden.
    Comparative evaluation of anti-EFGR affibody molecules labelled with gallium-68 and zirconium-89 using desferrioxamine B as a chelator2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no Supplement 1, p. S674-S675Article in journal (Other academic)
  • 36.
    Oroujeni, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Andersson, Ken G.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Lofblom, John
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Preclinical Evaluation of [Ga-68]Ga-DFO-ZEGFR:2377: A Promising Affibody-Based Probe for Noninvasive PET Imaging of EGFR Expression in Tumors2018In: CELLS, E-ISSN 2073-4409, Vol. 7, no 9, article id 141Article in journal (Refereed)
    Abstract [en]

    Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide Ga-68. Stability, specificity of binding to EGFR-expressing cells, and processing of [Ga-68]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [Ga-68]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [Zr-89]Zr-DFO-ZEGFR:2377. DFO-ZEGFR:2377 was efficiently (isolated yield of 73 +/- 3%) and stably labeled with Ga-68. Binding of [Ga-68]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [Ga-68]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [Zr-89]Zr-DFO-ZEGFR:2377, [Ga-68]Ga-DFO-ZEGFR:2377 demonstrated significantly (p < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [Ga-68]Ga-DFO-ZEGFR:2377. In conclusion, [Ga-68]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression.

  • 37.
    Rinne, Sara S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Leitao, Charles Dahlsson
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Bass, Tarek Z.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Andersson, Ken G.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Stahl, Stefan
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Lofblom, John
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Optimization of HER3 expression imaging using affibody molecules: Influence of chelator for labeling with indium-1112019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 655Article in journal (Refereed)
    Abstract [en]

    Radionuclide molecular imaging of human epidermal growth factor receptor 3 (HER3) expression using affibody molecules could be used for patient stratification for HER3-targeted cancer therapeutics. We hypothesized that the properties of HER3-targeting affibody molecules might be improved through modification of the radiometal-chelator complex. Macrocyclic chelators NOTA (1,4,7-triazacyclononane-N,N',N ''-triacetic acid), NODAGA (1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid), and DOTAGA (1,4,7,10-tetraazacyclododececane, 1-(glutaric acid)-4,7,10-triacetic acid) were conjugated to the C-terminus of anti-HER3 affibody molecule Z(08698) and conjugates were labeled with indium-111. All conjugates bound specifically and with picomolar affinity to HER3 in vitro. In mice bearing HER3-expressing xenografts, no significant difference in tumor uptake between the conjugates was observed. Presence of the negatively charged In-111-DOTAGA-complex resulted in the lowest hepatic uptake and the highest tumor-to-liver ratio. In conclusion, the choice of chelator influences the biodistribution of indium-111 labeled anti-HER3 affibody molecules. Hepatic uptake of anti-HER3 affibody molecules could be reduced by the increase of negative charge of the radiometal-chelator complex on the C-terminus without significantly influencing the tumor uptake.

  • 38.
    Rinne, Sara S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Leitao, C. Dahlsson
    KTH Royal Inst Technol, Stockholm, Sweden.
    Ståhl, S.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Optimization of affibody molecule for imaging of HER3 expression: negatively charged metal-chelator complex increases imaging contrast2017In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, p. S539-S540Article in journal (Other academic)
  • 39.
    Rinne, Sara S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Leitao, C. Dahlsson
    KTH Royal Inst Technol, Stockholm, Sweden.
    Andersson, K.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Optimization of molecular design of Ga-68-labeled affibody molecule for PET imaging of HER3 expression2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no Supplement 1, p. S109-S109Article in journal (Other academic)
  • 40.
    Rosestedt, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Andersson, K.
    Lofblom, J.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Stahl, S.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    PET Imaging of HER3-Expression in Tumours Using a 68Ga-Labeled Affibody Molecule2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S310-S310, article id OP677Article in journal (Other academic)
  • 41.
    Rosestedt, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Andersson, Ken G
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, John
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Ståhl, Stefan
    Evaluation of radiocobalt-labelled affibody molecule for imaging of human epidermal growth factor receptor 3 expression2017In: International Journal of Oncology, ISSN 1019-6439, Vol. 51, no 6, p. 1765-1774Article in journal (Refereed)
    Abstract [en]

    The human epidermal growth factor receptor 3 (HER3) is involved in the development of cancer resistance towards tyrosine kinase-targeted therapies. Several HER3‑targeting therapeutics are currently under clinical evaluation. Non-invasive imaging of HER3 expression could improve patient management. Affibody molecules are small engineered scaffold proteins demonstrating superior properties as targeting probes for molecular imaging compared with monoclonal antibodies. Feasibility of in vivo HER3 imaging using affibody molecules has been previously demonstrated. Preclinical studies have shown that the contrast when imaging using anti-HER3 affibody molecules can be improved over time. We aim to develop an agent for PET imaging of HER3 expression using the long-lived positron-emitting radionuclide cobalt-55 (55Co) (T1/2=17.5 h). A long-lived cobalt isotope 57Co was used as a surrogate for 55Co in this study. The anti-HER3 affibody molecule HEHEHE-ZHER3-NOTA was labelled with radiocobalt with high yield, purity and stability. Biodistribution of 57Co-HEHEHE-ZHER3-NOTA was measured in mice bearing DU145 (prostate carcinoma) and LS174T (colorectal carcinoma) xenografts at 3 and 24 h post injection (p.i.). Tumour-to-blood ratios significantly increased between 3 and 24 h p.i. (p<0.05). At 24 h p.i., tumour-to-blood ratios were 6 for DU145 and 8 for LS174T xenografts, respectively. HER3‑expressing xenografts were clearly visualized in a preclinical imaging setting already 3 h p.i., and contrast further improved at 24 h p.i. In conclusion, the radiocobalt-labelled anti-HER3 affibody molecule, HEHEHE-ZHER3-NOTA, is a promising tracer for imaging of HER3 expression in tumours.

  • 42.
    Rosestedt, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Andersson, Ken G.
    KTH Royal Inst Technol, Div Prot Technol, Stockholm, Sweden..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lofblom, John
    KTH Royal Inst Technol, Div Prot Technol, Stockholm, Sweden..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Stahl, Stefan
    KTH Royal Inst Technol, Div Prot Technol, Stockholm, Sweden..
    Affibody-mediated PET imaging of HER3 expression in malignant tumours2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15226Article in journal (Refereed)
    Abstract [en]

    Human epidermal growth factor receptor 3 (HER3) is involved in the progression of various cancers and in resistance to therapies targeting the HER family. In vivo imaging of HER3 expression would enable patient stratification for anti-HER3 immunotherapy. Key challenges with HER3-targeting are the relatively low expression in HER3-positive tumours and HER3 expression in normal tissues. The use of positron-emission tomography (PET) provides advantages of high resolution, sensitivity and quantification accuracy compared to SPECT. Affibody molecules, imaging probes based on a non-immunoglobulin scaffold, provide high imaging contrast shortly after injection. The aim of this study was to evaluate feasibility of PET imaging of HER3 expression using Ga-68-labeled affibody molecules. The anti-HER3 affibody molecule HEHEHE-Z08698-NOTA was successfully labelled with Ga-68 with high yield, purity and stability. The agent bound specifically to HER3-expressing cancer cells in vitro and in vivo. At 3 h pi, uptake of Ga-68-HEHEHE-Z08698-NOTA was significantly higher in xenografts with high HER3 expression (BT474, BxPC-3) than in xenografts with low HER3 expression (A431). In xenografts with high expression, tumour-to-blood ratios were >20, tumour-to-muscle >15, and tumour-to-bone >7. HER3-positive xenografts were visualised using microPET 3 h pi. In conclusion, PET imaging of HER3 expression is feasible using Ga-68-HEHEHE-Z08698-NOTA shortly after administration.

  • 43.
    Rosestedt, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Uppsala Univ, Dept Med Chem, Div Mol Imaging, Uppsala, Sweden..
    Andersson, K. G.
    Royal Inst Technol, KTH, Div Prot Technol, Stockholm, Sweden..
    Löfblom, J.
    Royal Inst Technol, KTH, Div Prot Technol, Stockholm, Sweden..
    Ståhl, S.
    Royal Inst Technol, KTH, Div Prot Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Development and Evaluation of Radiocobalt-labelled Affibody Molecule for Next Day PET Imaging of HER3 Expression2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S37-S38Article in journal (Refereed)
  • 44.
    Stevens, Marc
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Chow, Chow
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bogdan, Mitran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Åberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Odell, Luke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO2016In: ChemistryOpen, ISSN 2191-1363, Vol. 58, no 3, p. 566-573Article in journal (Refereed)
    Abstract [en]

    Herein we describe the development of new methodologyfocusing on 11C-labelling of sulfonyl carbamates in a multicomponentreaction comprising a sulfonyl azide, an alkyl alcohol and [11C]CO. Anumber of 11C-labelled sulfonyl carbamates were synthesised andisolated, and the developed methodology was then applied in thepreparation of a biologically active molecule. The target compoundwas obtained in 18±8% isolated radiochemical yield and wasevaluated for binding properties in a tumor cell assay, as well asundergoing in vivo biodistribution and imaging studies. Thisrepresents the first successful radiolabelling of C21, a non-peptideangiotensin II receptor subtype 2 agonist currently in clinical trials.

  • 45.
    Stevens, Marc Y.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Chow, Shiao Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Åberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of C-11-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [C-11]CO2016In: ChemistryOpen, ISSN 2191-1363, Vol. 5, no 6, p. 566-573Article in journal (Refereed)
    Abstract [en]

    We describe the development of a new methodology focusing on C-11-labeling of sulfonyl carbamates in a multicomponent reaction comprised of a sulfonyl azide, an alkyl alcohol, and [C-11] CO. A number of C-11-labeled sulfonyl carbamates were synthesized and isolated, and the developed methodology was then applied in the preparation of a biologically active molecule. The target compound was obtained in 24 +/- 10% isolated radiochemical yield and was evaluated for binding properties in a tumor cell assay; in vivo biodistribution and imaging studies were also performed. This represents the first successful radiolabeling of a non-peptide angiotensin II receptor subtype 2 agonist, C21, currently in clinical trials for the treatment of idiopathic pulmonary fibrosis.

  • 46.
    Summer, D
    et al.
    Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Oroujeni, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Andersson, K. G.
    Division of Protein Technology, KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, J.n
    Division of Protein Technology, KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Decristoforo, C
    Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
    PP15 89Zr-Siderophore-Affibody conjugates for imaging EGFR expression2018In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 8, no S1, article id 5Article in journal (Other academic)
    Abstract [en]

    Aim: Zirconium-89 has gained great interest for PET, when imaging at late time points is required. Desferrioxamine B (DFO), is mostly used for this radionuclide as bifunctional chelator (BFC) and we recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study reports on the comparison of FSC and DFO as BFCs for 89Zr labelling of the affibody ZEGFR:2377 targeting Epidermal Growth Factor Receptors (EGFR).

    Methods: FSC-ZEGFR:2377 and DFO-ZEGFR:2377 were evaluated regarding labeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution and microPET-CT imaging.

    Results: Both conjugates showed increased labelling yields at elevated temperature (85°C). Both conjugates revealed remarkable specificity, affinity and slow cell-line dependent internalisation. Labeling at 85°C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake but clear improvement as compared to 89Zr-DFO-ZEGFR:2377, labeled at room temperature, which was confirmed by MicroPET-CT imaging.

    Conclusion: We were able to show that FSC is a suitable alternative to DFO for labeling of biomolecules with zirconium-89. Furthermore our findings indicate that 89Zr- labeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

  • 47.
    Summer, Dominik
    et al.
    Med Univ Innsbruck, Dept Nucl Med, Anichstr 35, A-6020 Innsbruck, Austria..
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Oroujeni, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Andersson, Ken G.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Decristoforo, Clemens
    Med Univ Innsbruck, Dept Nucl Med, Anichstr 35, A-6020 Innsbruck, Austria..
    Cyclic versus Noncyclic Chelating Scaffold for Zr-89-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression2018In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 1, p. 175-185Article in journal (Refereed)
    Abstract [en]

    Zirconium-89 is an emerging radionuclide for positron emission tomography (PET) especially for biomolecules with slow e pharmacokinetics as due to its longer half-life, in comparison to fluorine 18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to head as bifunctional chelators for "Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates. FSC-ZEGFR:2377 and DFOZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temperature but radiochemical yields increased substantially at elevated temperature, 85 degrees C. Both 89Zr-FSC-ZEGFR:2377 and Zr-89-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell-line dependent internalization. Radiolabeling at 85 degrees C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89ZrDFO-ZEGFR:2377, radiolabeled at room temperature, showed a significant difference regarding tumor-to-organ ratios. MicroPET-CT imaging studies of Zr-89-FSC-ZEGFR:2377 as well as Zr-89-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomolecules with zirconium-89. Furthermore, our findings indicate that Zr-89-radiolabeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

  • 48.
    Varasteh, Zohreh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    The effect of macrocyclic chelators on the targeting properties of the 68Ga-labeled gastrin releasing peptide receptor antagonist PEG2-RM262015In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 42, no 5, p. 446-454Article in journal (Refereed)
    Abstract [en]

    Introduction

    Overexpression of gastrin-releasing peptide receptors (GRPR) has been reported in several cancers. Bombesin (BN) analogs are short peptides with a high affinity for GRPR. Different BN analogs were evaluated for radionuclide imaging and therapy of GRPR-expressing tumors. We have previously investigated an antagonistic analog of BN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to NOTA via a PEG2 spacer (NOTA-PEG2-RM26) labeled with 68Ga, 111In and Al18F. 68Ga-labeled NOTA-PEG2-RM26 showed high tumor-to-organ ratios.

    Methods

    The influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of 68Ga-labeled PEG2-RM26 was studied in vitro and in vivo.

    Results

    All conjugates were labeled with generator-produced 68Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC50 values of natGa-X-PEG2-RM26 (X = NOTA, DOTA, NODAGA, DOTAGA) were 2.3 ± 0.2, 3.0 ± 0.3, 2.9 ± 0.3 and 10.0 ± 0.6 nM, respectively. The internalization of the conjugates by PC-3 cells was low. However, the DOTA-conjugated analog demonstrated a higher internalization rate compared to other analogs. GRPR-specific uptake was found in receptor-positive normal tissues and PC-3 xenografts for all conjugates. The biodistribution of the conjugates was influenced by the choice of the chelator moiety. Although all radiotracers cleared rapidly from the blood, [68Ga]Ga-NOTA-PEG2-RM26 showed significantly lower uptake in lung, muscle and bone compared to the other analogs. The uptake in tumors (5.40 ± 1.04 %ID/g at 2 h p.i.) and the tumor-to-organ ratios (25 ± 3, 157 ± 23 and 39 ± 4 for blood, muscle and bone, respectively) were significantly higher for the NOTA-conjugate than the other analogs.

    Conclusions

    Chelators had a clear influence on the biodistribution and targeting properties of 68Ga-labeled antagonistic BN analogs. Positively charged [68Ga]Ga-NOTA-PEG2-RM26 provided a low kidney radioactivity uptake, high affinity, high tumor uptake and high image contrast.

  • 49.
    Vorobyeva, Anzhelika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Bragina, O.
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Tomsk, Russia.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Shulga, A.
    Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia.
    Proshkina, G.
    Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia.
    Chernov, V.
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Tomsk, Russia; Natl Res Tomsk Polytech Univ, Tomsk, Russia.
    Deyev, S.
    Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia; Natl Res Tomsk Polytech Univ, Tomsk, Russia; Natl Res Nucl Univ MEPhI, Moscow, Russia.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Molecular Imaging of HER2 Expression in Cancer Using SPECT2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no Supplement 1, p. S678-S679Article in journal (Other academic)
  • 50.
    Vorobyeva, Anzhelika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Bragina, Olga
    Russian Acad Sci, Canc Res Inst, Nucl Med Dept, Tomsk Natl Res Med Ctr, Tomsk, Russia.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Shulga, Alexey
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia.
    Proshkina, Galina
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia.
    Chernov, Vladimir
    Russian Acad Sci, Canc Res Inst, Nucl Med Dept, Tomsk Natl Res Med Ctr, Tomsk, Russia;Natl Res Tomsk Polytech Univ, Tomsk, Russia.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Deyev, Sergey
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia;Natl Res Tomsk Polytech Univ, Tomsk, Russia;Natl Res Nucl Univ MEPhI, Bionanophoton Lab, Inst Engn Phys Biomed PhysBio, Moscow, Russia.
    Comparative Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Radionuclide Molecular Imaging of HER2 Expression in Malignant Tumors2018In: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, article id 6930425Article in journal (Refereed)
    Abstract [en]

    High expression of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal carcinomas is a predictive biomarker for treatment using HER2-targeted therapeutics (antibodies trastuzumab and pertuzumab, antibody-drug conjugate trastuzumab DM1, and tyrosine kinase inhibitor lapatinib). Radionuclide molecular imaging of HER2 expression might permit stratification of patients for HER2-targeting therapies. In this study, we evaluated a new HER2-imaging probe based on the designed ankyrin repeat protein (DARPin) 9_29. DARPin 9_29 was labeled with iodine-125 by direct radioiodination and with [Tc-99m] Tc(CO)(3) using the C-terminal hexahistidine tag. DARPin 9_29 preserved high specificity and affinity of binding to HER2-expressing cells after labeling. Uptake of [I-125] I-DARPin 9_29 and [Tc-99m] Tc(CO)(3)-DARPin 9_29 in HER2-positive SKOV-3 xenografts in mice at 6 h after injection was 3.4 +/- 0.7 % ID/g and 2.9 +/- 0.7 % ID/g, respectively. This was significantly (p < 0.00005) higher than the uptake of the same probes in HER2-negative Ramos lymphoma xenografts, 0.22 +/- 0.09 % ID/g and 0.30 +/- 0.05 % ID/g, respectively. Retention of [I-125] I-DARPin 9_29 in the lung, liver, spleen, and kidneys was appreciably lower compared with [Tc-99m] Tc(CO)(3)-DARPin 9_29, which resulted in significantly (p < 0.05) higher tumor-to-organ ratios. The biodistribution data were confirmed by SPECT/CT imaging. In conclusion, radioiodine is a preferable label for DARPin 9_29.

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