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  • 1. Altai, M.
    et al.
    Ding, H.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Rinne, S.
    Dept Med Chem, Uppsala, Sweden..
    Vorobyeva, A.
    Graslund, T.
    Dept Prot Sci, Stockholm, Sweden..
    Tolmachev, V.
    Orlova, A.
    Dept Med Chem, Uppsala, Sweden..
    Evaluation Of Several Newly Designed Affibody-based Drug Conjugates Using Radionuclide-based Techniques: A Powerful Tool For Drug Development2019In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no SUPPL 1, p. S715-S716Article in journal (Other academic)
  • 2. Altai, M.
    et al.
    Honarvar, H.
    Wallberg, H.
    Strand, J.
    Varasteh, Z.
    Orlova, A.
    Dunas, F.
    Sandstrom, M.
    Rosestedt, M.
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with Re-1882013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, p. S219-S220Article in journal (Other academic)
  • 3.
    Altai, M.
    et al.
    Uppsala Univ, Imuunol Genet & Pathol, Uppsala, Sweden..
    Liu, Hao
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Div Prot Technol, Stockholm, Sweden..
    Orlova, A.
    Div Mol Imaging, Dept Med Chem, Uppsala, Sweden..
    Tolmachev, V.
    Uppsala Univ, Imuunol Genet & Pathol, Uppsala, Sweden..
    Gräslund, Torbjörn
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Div Prot Technol, Stockholm, Sweden..
    Improving of molecular design of a novel Affibody-fused HER2-recognising anticancer toxin using radionuclide-based techniques2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S178-S178Article in journal (Other academic)
  • 4. Altai, M.
    et al.
    Perols, Anna
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Sandström, M.
    Boschetti, F.
    Orlova, A.
    Tolmachev, V.
    Evaluation of a maleimido derivative of NODAGA for site-specific In-111-labeling of Affibody molecules2011In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 38, p. S146-S146Article in journal (Other academic)
  • 5. Altai, M.
    et al.
    Strand, J.
    Rosik, Daniel
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Selvaraju, R.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Orlova, A.
    Tolmachev, V.
    Comparative evaluation of anti-HER2 affibody molecules labeled with 68Ga and 111In using maleimido derivatives of DOTA and NODAGA.2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, p. S299-S299Article in journal (Refereed)
  • 6. Altai, M.
    et al.
    Tsourma, M.
    Mitran, B.
    Honarvar, H.
    Perols, Anna
    KTH, School of Biotechnology (BIO), Protein Technology.
    Robillard, M.
    Rossin, R.
    ten Hoeve, W.
    Sandstrom, M.
    Orlova, A.
    Karlström, Amelie Eriksson
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    Affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting: proof-of-principle.2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, p. S246-S246Article in journal (Refereed)
  • 7.
    Altai, M.
    et al.
    Immunology, Genetics and Pathology, Uppsala, SWEDEN, .
    Vorobyeva, A.
    Immunology, Genetics and Pathology, Uppsala, SWEDEN, .
    Westerlund, Kristina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Mitran, B.
    Div Mol Imaging, Uppsala, Sweden..
    Orlova, A.
    Div Mol Imaging, Uppsala, Sweden..
    Eriksson Karlström, Amelie
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Tolmachev, V.
    Immunology, Genetics and Pathology, Uppsala, SWEDEN, .
    A novel method for conjugation of PNA to antibodies for radionuclide based pretargeting: proof of principal2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S648-S648Article in journal (Other academic)
  • 8. Altai, M.
    et al.
    Wallberg, H.
    Honarvar, H.
    Strand, J.
    Orlova, A.
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    Varasteh, Z.
    Sandström, M.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    Re-188-Z(HER2: V2), a promising targeting agent against HER2-expressing tumors: in vitro and in vivo assessment2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, p. S119-S119Article in journal (Other academic)
  • 9. Altai, M.
    et al.
    Westerlund, Kristina
    KTH, School of Biotechnology (BIO), Protein Technology.
    Velletta, J.
    Honarvar, H.
    Orlova, A.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    Comparative evaluation of Lu-177-HP2 and In-111-HP2, secondary agents for affibody-based PNA-mediated radionuclide pretargeting2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S237-S237Article in journal (Refereed)
  • 10.
    Andersson, Ken G.
    et al.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Varasteh, Z.
    Rosenstedt, M.
    Rosestedt, M.
    Malm, M.
    KTH.
    Sandström, M.
    KTH.
    Tolmachev, V.
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Orlova, A.
    111In-labeled NOTA-conjugated Affibody molecules for visualization of HER3 expression in malignant tumors2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, p. S311-S311Article in journal (Other academic)
  • 11.
    Ekblad, Torun
    et al.
    KTH, School of Biotechnology (BIO).
    Tran, Thuy
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Orlova, Anna
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Widström, Charles
    Section of Hospital Physics, Department of Oncology, Uppsala University Hospital.
    Feldwisch, Joachim
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Abrahmsén, Lars
    Affibody AB, Bromma.
    Wennborg, Anders
    Affibody AB, Bromma.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO).
    Tolmachev, Vladimir
    Unit of Nuclear Medicine, Department of Medical Sciences, Uppsala University.
    Development and preclinical characterisation of 99mTc-labelled Affibody molecules with reduced renal uptake2008In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 35, no 12, p. 2245-2255Article in journal (Refereed)
    Abstract [en]

    Purpose  Affibody molecules are low molecular weight proteins (7 kDa), which can be selected to bind to tumour-associated target proteins with subnanomolar affinity. Because of rapid tumour localisation and clearance from nonspecific compartments, Affibody molecules are promising tracers for molecular imaging. Earlier, 99mTc-labelled Affibody molecules demonstrated specific targeting of tumour xenografts. However, the biodistribution was suboptimal either because of hepatobiliary excretion or high renal uptake of the radioactivity. The goal of this study was to optimise the biodistribution of Affibody molecules by chelator engineering. Materials and methods  Anti-HER2 ZHER2:342 Affibody molecules, carrying the mercaptoacetyl-glutamyl-seryl-glutamyl (maESE), mercaptoacetyl-glutamyl-glutamyl-seryl (maEES) and mercaptoacetyl-seryl-glutamyl-glutamyl (maSEE) chelators, were prepared by peptide synthesis and labelled with 99mTc. The tumour-targeting capacity of these conjugates was compared with each other and with the best previously available conjugate, 99mTc-maEEE-ZHER2:342, in nude mice bearing SKOV-3 xenografts. The tumour-targeting capacity of the most promising conjugate, 99mTc-maESE-ZHER2:342, was compared with radioiodinated ZHER2:342. Results  All novel conjugates demonstrated successful tumour targeting and a low degree of hepatobiliary excretion. The renal uptakes of serine-containing conjugates, 33 ± 5, 68 ± 21 and 71 ± 10%IA/g, for99mTc-maESE-ZHER2:342, 99mTc-maEES-ZHER2:342 and 99mTc-maSEE-ZHER2:342, respectively, were significantly reduced in comparison with 99mTc-maEEE-ZHER2:342 (102 ± 13%IA/g). For 99mTc-maESE-ZHER2:342, a tumour uptake of 9.6 ± 1.8%IA/g and a tumour-to-blood ratio of 58 ± 6 were reached at 4 h p.i. Conclusions  A combination of serine and glutamic acid residues in the chelator sequence confers increased renal excretion and relatively low renal uptake of 99mTc-labelled Affibody molecules. In combination with preserved targeting capacity, this improved imaging of targets in abdominal area.

  • 12.
    Engfeldt, Torun
    et al.
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Orlova, Anna
    Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Tran, Thuy
    Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Bruskin, Alexander
    Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Widström, Charles
    Department of Hospital Physics, Uppsala University Hospital.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Tolmachev, Vladimir
    Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Imaging of HER2-expressing tumours using a synthetic Affibody molecule containing the 99mTc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence2007In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 34, no 5, p. 722-733Article in journal (Refereed)
    Abstract [en]

    Purpose  Expression of human epidermal growth factor receptor type 2 (HER2) in malignant tumours possesses well-documented prognostic and predictive value. Non-invasive imaging of expression can provide valuable diagnostic information, thereby influencing patient management. Previously, we reported a phage display selection of a small (about 7 kDa) protein, the Affibody molecule ZHER2:342, which binds HER2 with subnanomolar affinity, and demonstrated the feasibility of targeting of HER2-expressing xenografts using radioiodinated ZHER2:342. The goal of this study was to develop a method for 99mTc labelling of ZHER2:342 using the MAG3 chelator, which was incorporated into ZHER2:342 using peptide synthesis, and evaluate the targeting properties of the labelled conjugate. Methods  MAG3-ZHER2:342 was assembled using Fmoc/tBu solid phase peptide synthesis. Biochemical characterisation of the agent was performed using RP-HPLC, ESI-MS, biosensor studies and circular dichroism. A procedure for 99mTc labelling in the presence of sodium/potassium tartrate was established. Tumour targeting was evaluated by biodistribution study and gamma camera imaging in xenograft-bearing mice. Biodistribution of 99mTc-MAG3-ZHER2:342 and 125I-para-iodobenzoate -ZHER2:342 was compared 6 h p.i. Results  Synthetic MAG3-ZHER2:342 possessed an affinity of 0.2 nM for HER2 receptors. The peptide was labelled with 99mTc with an efficiency of about 75–80%. Labelled 99mTc-MAG3-ZHER2:342 retained capacity to bind specifically HER2-expressing SKOV-3 cells in vitro. 99mTc-MAG3-ZHER2:342 showed specific tumour targeting with a contrast similar to a radioiodinated analogue in mice bearing LS174T xenografts. Gamma camera imaging demonstrated clear and specific visualisation of HER2 expression. Conclusion  Incorporation of a mercaptoacetyl-containing chelating sequence during chemical synthesis enabled site-specific 99mTc labelling of the ZHER2:342 Affibody molecule with preserved targeting capacity.

  • 13.
    Engfeldt, Torun
    et al.
    KTH, School of Biotechnology (BIO).
    Tran, Thuy
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Orlova, Anna
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Widström, Charles
    Section of Hospital Physics, Department of Oncology, Uppsala University Hospital.
    Feldwisch, Joachim
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Abrahmsén, Lars
    Affibody AB, Bromma.
    Wennborg, Anders
    Affibody AB, Bromma.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO).
    Tolmachev, Vladimir
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule2007In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 34, no 11, p. 1843-1853Article in journal (Refereed)
    Abstract [en]

    Purpose  Monitoring HER2 expression is crucial for selection of breast cancer patients amenable to HER2-targeting therapy. The Affibody molecule ZHER2:342 binds to HER2 with picomolar affinity and enables specific imaging of HER2 expression. Previously, ZHER2:342 with the additional N-terminal mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) sequence was labelled with 99mTc and demonstrated specific targeting of HER2-expressing xenografts. However, hepatobiliary excretion caused high radioactivity accumulation in the abdomen. We investigated whether the biodistribution of ZHER2:342 can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues.

    Methods  The Affibody molecule ZHER2:342, carrying the chelators mercaptoacetyl-glycyl-seryl-glycyl (maGSG), mercaptoacetyl-glycyl-D-seryl-glycyl [maG(D-S)G] and mercaptoacetyl-seryl-seryl-seryl (maSSS), were prepared by peptide synthesis and labelled with 99mTc. The differences in the excretion pathways were evaluated in normal mice. The tumour targeting capacity of 99mTc-maSSS-ZHER2:342 was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated ZHER2:342.

    Results  A shift towards renal excretion was obtained when glycine was substituted with serine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced threefold for the maSSS conjugate in comparison with the maGGG conjugate 4 h post injection (p.i.). The tumour uptake of 99mTc-maSSS-ZHER2:342 was 11.5 ± 0.5% IA/g 4 h p.i., and the tumour-to-blood ratio was 76. The pharmacokinetics and uptake characteristics of technetium-labelled ZHER2:342 were better than those of radioiodinated ZHER2:342.

    Conclusion  The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule ZHER2:342 compared with glycyl-containing chelators and is favourable for imaging of tumours and metastases in the abdominal area.

  • 14. Garousi, J.
    et al.
    Anderson, Ken
    KTH, School of Biotechnology (BIO), Protein Technology.
    Dam, J. H.
    Olsen, B. B.
    Orlova, A.
    Buijs, J.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Thisgaard, H.
    Tolmachev, V.
    The use of radiocobalt as a label improves PET imaging of EGFR using DOTA-conjugated affibody molecules2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, p. S244-S244Article in journal (Refereed)
  • 15. Garousi, J.
    et al.
    Honarvar, H.
    Andersson, K.
    KTH.
    Mitran, B.
    Orlova, A.
    Buijs, J.
    Frejd, F. Y.
    Tolmachev, V.
    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)
  • 16.
    Garousi, J.
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Huizing, F.
    Radboud Univ Nijmegen, Dept Radiat Oncol, Med Ctr, Nijmegen, Netherlands..
    Vorobyeva, A.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Mitran, B.
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Andersson, K.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Leitao, Charles Dahlsson
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Frejd, F.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Bussink, J.
    Radboud Univ Nijmegen, Dept Radiat Oncol, Med Ctr, Nijmegen, Netherlands..
    Orlova, A.
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Heskamp, S.
    Radboud Univ Nijmegen, Dept Radiol & Nucl Med, Med Ctr, Nijmegen, Netherlands..
    Tolmachev, V.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Comparison Of Affibody- And Antibody Fragments-based Caix Imaging Probes In Mice Bearing Renal Cell Carcinoma Xenografts2019In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no SUPPL 1, p. S80-S80Article in journal (Other academic)
  • 17. Garousi, J.
    et al.
    Lindbo, S.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Honarvar, H.
    Velletta, J.
    Mitran, B.
    Altai, M.
    Orlova, A.
    Tolmachev, V.
    Hober, Sophia
    KTH, School of Biotechnology (BIO), Protein Technology.
    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)
  • 18.
    Garousi, J.
    et al.
    Uppsala Univ, Uppsala, Sweden..
    Lindbo, Sarah
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Mitran, B.
    Uppsala Univ, Uppsala, Sweden..
    Vorobyeva, A.
    Uppsala Univ, Uppsala, Sweden..
    Oroujeni, M.
    Uppsala Univ, Uppsala, Sweden..
    Orlova, A.
    Uppsala Univ, Uppsala, Sweden..
    Hober, Sophia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Tolmachev, V.
    Uppsala Univ, Uppsala, Sweden..
    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)
  • 19. Garousi, J.
    et al.
    Lindbo, Sarah
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Orlova, A.
    Åstrand, Mikael
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Nilvebrant, Johan
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Buijs, J.
    Sandstrom, M.
    Honarvar, H.
    Tolmachev, V.
    Hober, Sophia
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Development of ADAPT6 as a new scaffold protein for radionuclide molecular imaging2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, p. S309-S309Article in journal (Refereed)
  • 20.
    Garousi, J.
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    von Witting, Emma
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Lindbo, Sarah
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Vorobyeva, A.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Altai, M.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Oroujeni, M.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Mitran, B.
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Orlova, A.
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Hober, Sophia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Tolmachev, V.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Selection Of The Optimal Macrocyclic Chelators For Labelling With In-111 And Ga-68 Improves Contrast Of Her2 Imaging Using Engineered Scaffold Protein Adapt62019In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no SUPPL 1, p. S131-S131Article in journal (Other academic)
  • 21. Honarvar, H.
    et al.
    Muller, C.
    van der Meulen, N.
    Cohrs, S.
    Westerlund, K.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO).
    Schibli, R.
    Tolmachev, V.
    Development and application of first Sc-44-labeled Affibody molecule2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S177-S177Article in journal (Refereed)
  • 22. Honarvar, H.
    et al.
    Perols, Anna
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Strand, J.
    Selvaraju, R.
    Orlova, A.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Tolmachev, V.
    Influence of DOTA chelator position on biodistribution and targeting properties of 111 In-labelled anti-HER2 affibody molecules2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, p. S263-S263Article in journal (Other academic)
  • 23. Honarvar, H.
    et al.
    Strand, J.
    Perols, Anna
    KTH, School of Biotechnology (BIO), Protein Technology.
    Orlova, A.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    Influence of DOTA chelator position on biodistribution and targeting properties of 68Ga-labeled synthetic anti-HER2 Affibody molecules. Comparison with 111In-labeled counterparts2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, p. S245-S246Article in journal (Other academic)
  • 24. Honarvar, H.
    et al.
    Westerlund, Kristina
    KTH, School of Biotechnology (BIO), Protein Technology.
    Altai, M.
    Sandstrom, M.
    Orlova, A.
    Tolmachev, V.
    Karlstrom, A. Eriksson
    Feasibility of Affibody molecule-based PNA-mediated pretargeting2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, p. S101-S102Article in journal (Refereed)
  • 25.
    Lindbo, Sarah
    et al.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Garousi, J.
    Åstrand, Mikael
    KTH, School of Biotechnology (BIO), Protein Technology.
    Honarvar, H.
    Orlova, A.
    Hober, S.
    Tolmachev, V.
    Influence of Histidine-Containing Tags on Biodistribution of Radiolabelled ADAPT-Based Imaging Probes2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, p. S100-S100Article in journal (Refereed)
    Abstract [en]

    Aim. ADAPTs are a class of small ( ∼ 5 kDa) robust scaffold proteins suitable as probes for radionuclide molecular imaging in vivo. The attachment of a histidine-containing tags to the scaffold proteins allows efficient purification by immobilized metal ion affinity chromatography (IMAC) and permits labelling with 99mTc(CO)3. Earlier, we have demonstrated that replacement of the hexahistidine (H6)-tag with the negatively charged histidine-glutamate-histidine-glutamate-histidine-glutamate (HE3)-tag reduces hepatic uptake of radiolabelled affibody molecules. The same effect has been confirmed for other scaffold proteins, DARPins, and short peptides. The aim of this study was to evaluate effect of histidine-containing tag composition on biodistribution of ADAPTs. Material and methods. A series of anti-HER2 ADAPT6 probes having DEAVDANS lead sequence and H6- or HE3-tags at N-termini has been prepared. In two variants, maleimido derivative of DOTA was conjugated to a unique cysteine was incorporated at N-terminus. DOTA-C-HE3-ADAPT6 and DOTA-C-H6-ADAPT6 were labelled with 111In. HE3-ADAPT6 and H6-ADAPT6 were labelled with 99mTc(CO)3using IsoLink kit. Binding specificity, affinity, and cellular processing of new conjugates was evaluated using HER2-expressing SKOV-3 ovarian carcinoma cells. Biodistribution at 1,4 and 24 h p.i. was evaluated in normal NMRI mice. Tumour-targeting properties of the best 99mTc(CO) 3-labelled variant, 99mTc(CO)3-H6-ADAPT6 were evaluated in BALB/C nu/nu mice bearing SKOV-3 xenografts. Results. All radiolabeled ADAPTs demonstrated specific binding to SKOV-3 cells with affinities in the range of 1.1-2.8 nM. The internalization by SKOV-3 cells was slow. In vivo, all conjugates cleared rapidly from blood via kidneys with subsequent renal re-absorption. The hepatic uptake of 111In-DOTA-C-H6-ADAPT6 was slightly but significantly (p<0.05) higher that the uptake of 111In-DOTA-C-HE3-ADAPT6 at 1 h pi, but biodistribution was very similar at later time points. Surprisingly, the uptake of 99mTc(CO)3-HE3-ADAPT6 was significantly (p<0.05) higher than uptake of 99mTc(CO)3-H6-ADAPT6 in liver, blood, and bone at 1h p.i. At 4 h p.i., hepatic uptakes were equal, but 99mTc(CO)3-H6-ADAPT6 provided lower uptake in blood and bone. 99mTc(CO)3-H6-ADAPT6 demonstrated high (19? 3 %ID/g at 4 h p.i.) and specific tumour uptake. Tumour-to-blood and tumour-to-liver ratios were 102? 29 and 12? 3, respectively. Conclusion. Influence of histidine-containing tag on biodistribution of scaffold proteins depends on composition of a scaffold protein and might differ appreciably. This should be take into account in molecular design of imaging probes based on engineered scaffold proteins

  • 26. Malmberg, Jennie
    et al.
    Perols, Anna
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Varasteh, Zohreh
    Altai, Mohamed
    Braun, Alexis
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Sandström, Mattias
    Garske, Ulrike
    Tolmachev, Vladimir
    Orlova, Anna
    Karlström, Amelie Eriksson
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with In-111 using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, no 3, p. 481-492Article in journal (Refereed)
    Abstract [en]

    Purpose In disseminated prostate cancer, expression of human epidermal growth factor receptor type 2 (HER2) is one of the pathways to androgen independence. Radionuclide molecular imaging of HER2 expression in disseminated prostate cancer might identify patients for HER2-targeted therapy. Affibody molecules are small (7 kDa) targeting proteins with high potential as tracers for radionuclide imaging. The goal of this study was to develop an optimal Affibody-based tracer for visualization of HER2 expression in prostate cancer. Methods A synthetic variant of the anti-HER2 Z(HER2:342) Affibody molecule, Z(HER2:S1), was N-terminally conjugated with the chelators DOTA, NOTA and NODAGA. The conjugated proteins were biophysically characterized by electrospray ionization mass spectroscopy (ESI-MS), circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis. After labelling with In-111, the biodistribution was assessed in normal mice and the two most promising conjugates were further evaluated for tumour targeting in mice bearing DU-145 prostate cancer xenografts. Results The HER2-binding equilibrium dissociation constants were 130, 140 and 90 pM for DOTA-Z(HER2:S1), NOTA-Z(HER2:S1) and NODAGA-Z(HER2:S1), respectively. A comparative study of In-111-labelled DOTA-Z(HER2:S1), NOTA-Z(HER2:S1) and NODAGA-Z(HER2:S1) in normal mice demonstrated a substantial influence of the chelators on the biodistribution properties of the conjugates. In-111-NODAGA-Z(HER2:S1) had the most rapid clearance from blood and healthy tissues. In-111-NOTA-Z(HER2:S1) showed high hepatic uptake and was excluded from further evaluation. In-111-DOTA-Z(HER2:S1) and In-111-NODAGAZHER2: S1 demonstrated specific uptake in DU-145 prostate cancer xenografts in nude mice. The tumour uptake of In-111-NODAGA-Z(HER2:S1), 5.6 +/- 0.4% ID/g, was significantly lower than the uptake of In-111-DOTA-Z(HER2:S1), 7.4 +/- 0.5% ID/g, presumably because of lower bioavailability due to more rapid clearance. In-111-NODAGA-Z(HER2:S1) provided higher tumour-to-blood ratio, but somewhat lower tumour-to-liver, tumour-to-spleen and tumour-to-bone ratios. Conclusion Since distant prostate cancer metastases are situated in bone or bone marrow, the higher tumour-to-bone ratio is the most important. This renders In-111-DOTA-Z(HER2:S1) a preferable agent for imaging of HER2 expression in disseminated prostate cancer.

  • 27. Mitran, B.
    et al.
    Altai, M.
    Hofström, Camilla
    KTH, School of Biotechnology (BIO), Protein Technology.
    Honarvar, H.
    Widstrom, C.
    Orlova, A.
    Tolmachev, V.
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Protein Technology.
    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, p. S440-S440Article in journal (Other academic)
  • 28. Mitran, B.
    et al.
    Güler, Rezan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Lindstrom, E.
    Fleetwood, Filippa
    KTH.
    Tolmachev, V.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO).
    Orlova, A.
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    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)
  • 29.
    Nag, S.
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Jia, Z.
    Karolinska Inst, Stockholm, Sweden..
    Datta, P.
    Karolinska Inst, Stockholm, Sweden..
    Azpiazu, P. M.
    Karolinska Inst, Stockholm, Sweden..
    Arakawa, R.
    Karolinska Inst, Stockholm, Sweden..
    Varnas, K.
    Karolinska Inst, Stockholm, Sweden..
    Lemoine, L.
    Karolinska Inst, Stockholm, Sweden..
    Guanglin, Kuang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Langstram, B.
    Uppsala Univ, Stockholm, Sweden..
    Halldin, C.
    Karolinska Inst, Stockholm, Sweden..
    Development of novel C-11- labeled ASEM analogs for detection of neuronal nicotinic acetylcholine receptors (alpha 7-nAChR)2019In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no SUPPL 1, p. S228-S228Article in journal (Other academic)
  • 30.
    Natarajan Arul, Murugan
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Chiotis, Konstantinos
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Neurol, Stockholm, Sweden..
    Rodriguez-Vieitez, Elena
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden..
    Lemoine, Laetitia
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden..
    Ågren, Hans
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. Uppsala Univ, Dept Phys & Astron, Box 516, SE-75120 Uppsala, Sweden..
    Nordberg, Agneta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Aging, Stockholm, Sweden..
    Cross-interaction of tau PET tracers with monoamine oxidase B: evidence from in silico modelling and in vivo imaging2019In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 6, p. 1369-1382Article in journal (Refereed)
    Abstract [en]

    PurposeSeveral tracers have been designed for tracking the abnormal accumulation of tau pathology in vivo. Recently, concerns have been raised about the sources of off-target binding for these tracers; inconclusive data propose binding for some tracers to monoamine oxidase B (MAO-B).MethodsMolecular docking and dynamics simulations were used to estimate the affinity and free energy for the binding of several tau tracers (FDDNP, THK523, THK5105, THK5317, THK5351, T807 [aka AV-1451, flortaucipir], T808, PBB3, RO-948, MK-6240, JNJ-311 and PI-2620) to MAO-B. These values were then compared with those for safinamide (MAO-B inhibitor). PET imaging was used with the tau tracer [F-18]THK5317 and the MAO-B tracer [C-11]DED in five patients with Alzheimer's disease to investigate the MAO-B binding component of this first generation tau tracer in vivo.ResultsThe computational modelling studies identified a binding site for all the tau tracers on MAO-B; this was the same site as that for safinamide. The binding affinity and free energy of binding for the tau tracers to MAO-B was substantial and in a similar range to those for safinamide. The most recently developed tau tracers MK-6240, JNJ-311 and PI-2620 appeared, in silico, to have the lowest relative affinity for MAO-B. The in vivo investigations found that the regional distribution of binding for [F-18]THK5317 was different from that for [C-11]DED, although areas of suspected off-target [F-18]THK5317 binding were detected. The binding relationship between [F-18]THK5317 and [C-11]DED depended on the availability of the MAO-B enzyme.ConclusionsThe developed tau tracers show in silico and in vivo evidence of cross-interaction with MAO-B; the MAO-B component of the tracer binding was dependent on the regional concentration of the enzyme.

  • 31.
    Nilvebrant, Johan
    et al.
    KTH, School of Biotechnology (BIO), Proteomics.
    Kuku, G.
    Björkelund, H.
    Nestor, M.
    Selection and characterisation of human CD44v6-binding antibody fragments for specific targeting of head and neck squamous cell carcinoma2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, p. S418-S418Article in journal (Other academic)
  • 32. Nordberg, E.
    et al.
    Friedman, M.
    Nilsson, F.
    Stahl, S.
    Glimelius, B.
    Orlova, A.
    Tolmachev, V.
    Carlsson, J.
    Biological characterization in vitro and in vivo of a new EGFR binding Affibody molecule2006In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 33, p. S284-S284Article in journal (Other academic)
  • 33.
    Orlova, A.
    et al.
    Uppsala Univ, Uppsala, Sweden..
    Friedman, M.
    KTH, School of Biotechnology (BIO).
    Sandstroem, M.
    Univ Uppsala Hosp, Uppsala, Sweden..
    Eriksson, T.
    Affibody AB, Bromma, Sweden..
    Ståhl, S.
    KTH, School of Biotechnology (BIO).
    Nilsson, F. Y.
    Affibody AB, Bromma, Sweden..
    Tolmachev, V.
    Affibody AB, Bromma, Sweden..
    Imaging of EGRF expression in xenografts using (111)InBz-DTPA-Z(1907) affibody molecule2007In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 34, p. S222-S222Article in journal (Other academic)
  • 34. Orlova, A.
    et al.
    Hofström, Camilla
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Malmberg, J.
    Ahlgren, S.
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Tolmachev, V.
    HEHEHE: a new chelator for [Tc-99m(CO)(3)](+)-labeling assembling His(6)-tag in protein purification2010In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 37, no Suppl. 2, p. S264-S265Article in journal (Other academic)
  • 35. Orlova, A.
    et al.
    Magnusson, M.
    Eriksson, T.
    Nilsson, M.
    Carlsson, J.
    Tolmachev, V.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Nilsson, F. Y.
    Effect of affinity maturation on biodistribution of radioiodinated anti-HER2 Affibody molecules2005In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 32, p. S78-S79Article in journal (Other academic)
  • 36. Orlova, A.
    et al.
    Malm, Malin
    KTH, School of Biotechnology (BIO), Protein Technology.
    Lindberg, Hanna
    KTH, School of Biotechnology (BIO), Protein Technology.
    Varasteh, Z.
    Selvaraju, R. K.
    Kronqvist, Nina
    KTH, School of Biotechnology (BIO), Protein Technology.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    Feasibility of radionuclide imaging of HER3-expressing tumours using technetium-99m labeled affibody molecules2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, p. S185-S186Article in journal (Other academic)
  • 37. Orlova, A.
    et al.
    Malmberg, J.
    Hofström, Camilla
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Abrahmsen, L.
    Bergman, T.
    Sjöberg, A.
    Sandström, M.
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Tolmachev, V.
    Affibody molecule 111In-DOTA-ZIGF1R:4551, a new potential probe for imaging of IGF-1R expression in malignant tumours2011In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 38, p. S171-S171Article in journal (Other academic)
  • 38. Orlova, A.
    et al.
    Rosestedt, M.
    Mitran, B.
    Bass, T.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Frejd, F. Y.
    Löfblom, J.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    Ståhl, S.
    KTH, School of Biotechnology (BIO), Protein Technology.
    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)
  • 39.
    Orlova, A.
    et al.
    Uppsala Univ, Uppsala, Sweden..
    Rosestedt, M.
    Uppsala Univ, Uppsala, Sweden..
    Rinne, S. S.
    Uppsala Univ, Uppsala, Sweden..
    Mitran, B.
    Uppsala Univ, Uppsala, Sweden..
    Vorobyeva, A.
    Uppsala Univ, Uppsala, Sweden..
    Andersson, Ken G.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Tolmachev, V.
    Uppsala Univ, Uppsala, Sweden..
    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, p. S673-S673Article in journal (Other academic)
  • 40. Orlova, Anna
    et al.
    Hofström, Camilla
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Strand, Joanna
    Varasteh, Zohreh
    Sandström, Mattias
    Andersson, Karl
    Tolmachev, Vladimir
    Gräslund, Torbjörn
    [99mTc(CO)3]+-(HE)3-Z IGF1R45514551: a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours.2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no 3, p. 439-449Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Radionuclide imaging of insulin-like growth factor type 1 receptor (IGF-1R) expression in tumours might be used for selection of patients who would benefit from IGF-1R-targeted therapy. We have previously shown the feasibility of IGF-1R imaging using the Affibody molecule (111)In-DOTA-His(6)-Z(IGF1R:4551). The use of (99m)Tc instead of (111)In should improve sensitivity and resolution of imaging, and reduce the dose burden to patients. We hypothesized that inclusion of a HEHEHE tag instead of a His(6) tag in Z(IGF1R:4551) would permit its convenient purification using IMAC, enable labelling with [(99m)Tc(CO)(3)](+), and improve its biodistribution. METHODS: Z(IGF1R:4551) was expressed with a HEHEHE tag in the N terminus. The resulting (HE)(3)-Z(IGF1R:4551) construct was labelled with [(99m)Tc(CO)(3)](+). Targeting of IGF-1R-expressing cells using [(99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) was evaluated in vitro and in vivo. RESULTS: (HE)(3)-Z(IGF1R:4551) was stably labelled with (99m)Tc with preserved specific binding to IGF-1R-expressing DU-145 prostate cancer cells in vitro. In mice, [(99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) accumulated in IGF-1R-expressing organs (pancreas, stomach, lung and salivary gland). [(99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) demonstrated 3.6-fold lower accumulation in the liver and spleen than (111)In-DOTA-Z(IGF1R:4551). In NMRI nu/nu mice with DU-145 prostate cancer xenografts, the tumour uptake was 1.32 ± 0.11 %ID/g and the tumour-to-blood ratio was 4.4 ± 0.3 at 8 h after injection. The xenografts were visualized using a gamma camera 6 h after injection. CONCLUSION: (99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) is a promising candidate for visualization of IGF-1R expression in malignant tumours.

  • 41. Orlova, Anna
    et al.
    Malm, Magdalena
    KTH, School of Biotechnology (BIO), Protein Technology.
    Rosestedt, Maria
    Varasteh, Zohreh
    Andersson, Ken
    KTH, School of Biotechnology (BIO), Protein Technology.
    Selvaraju, Ram Kumar
    Altai, Mohamed
    Honarvar, Hadis
    Strand, Joanna
    Stahl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, Vladimir
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    Imaging of HER3-expressing xenografts in mice using a Tc-99m(CO)(3)-HEHEHE-Z(HER3:08699) affibody molecule2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no 7, p. 1450-1459Article in journal (Refereed)
    Abstract [en]

    Human epidermal growth factor receptor type 3 (HER3) is a transmembrane receptor tyrosine kinase belonging to the HER (ErbB) receptor family. Membranous expression of HER3 is associated with trastuzumab resistance in breast cancer and the transition to androgen independence in prostate cancer. Imaging of HER3 expression in malignant tumors may provide important diagnostic information that can influence patient management. Affibody molecules with low picomolar affinity to HER3 were recently selected. The aim of this study was to investigate the feasibility of HER3 imaging using radiolabeled Affibody molecules. A HER3-binding Affibody molecule, Z(08699), with a HEHEHE-tag on N-terminus was labeled with Tc-99m(CO)(3) using an IsoLink kit. In vitro and in vivo binding specificity and the cellular processing of the labeled binder were evaluated. Biodistribution of Tc-99m(CO)(3)-HEHEHE-Z(08699) was studied over time in mice bearing HER3-expressing xenografts. HEHEHE-Z(08699) was labeled with Tc-99m(CO)(3) with an isolated yield of > 80 % and a purity of > 99 %. Binding of Tc-99m(CO)(3)-HEHEHE-Z(08699) was specific to BT474 and MCF7 (breast cancer), and LS174T (colon cancer) cells. Cellular processing showed rapid binding and relatively quick internalization of the receptor/Affibody molecule complex (70 % of cell-associated radioactivity was internalized after 24 h). The tumor targeting was receptor mediated and the excretion was predominantly renal. Receptor-mediated uptake was also found in the liver, lung, stomach, intestine, and salivary glands. At 4 h pi, tumor-to-blood ratios were 7 +/- 3 for BT474, and 6 +/- 2 for LS174T xenografts. LS174T tumors were visualized by microSPECT 4 h pi. The results of this study suggest the feasibility of HER3-imaging in malignant tumors using Affibody molecules.

  • 42. Orlova, Anna
    et al.
    Tran, Thuy A.
    Ekblad, Torun
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Tolmachev, Vladimir
    Re-186-maSGS-Z(HER2:342), a potential Affibody conjugate for systemic therapy of HER2-expressing tumours2010In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 37, no 2, p. 260-269Article in journal (Refereed)
    Abstract [en]

    Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z(HER2:342) has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for Tc-99m-labelling, we have found that synthetic Z(HER2:342) conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. maGGG-Z(HER2:342) and maGSG-Z(HER2:342) were labelled with Re-186 and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by Re-186-maGSG-Z(HER2:342) were studied. Gluconate-mediated labelling of maGGG-Z(HER2:342) and maGSG-Z(HER2:342) with Re-186 provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both Re-186-maGGG-Z(HER2:342) and Re-186-maGSG-Z(HER2:342) demonstrated lower renal uptake than their Tc-99m-labelled counterparts. Re-186-maGSG-Z(HER2:342) provided the lowest uptake in healthy tissues. Biodistribution of Re-186-maGSG-Z(HER2:342) in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84 +/- 0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.

  • 43. Oroujeni, M.
    et al.
    Andersson, K.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Garousi, J.
    Mitran, B.
    Orlova, A.
    Löfblom, J.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    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)
  • 44.
    Oroujeni, M.
    et al.
    Uppsala Univ, Uppsala, Sweden..
    Garousi, J.
    Uppsala Univ, Uppsala, Sweden..
    Andersson, Ken G.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Mitran, B.
    Uppsala Univ, Uppsala, Sweden..
    Orlova, A.
    Uppsala Univ, Uppsala, Sweden..
    Tolmachev, V.
    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, p. S674-S675Article in journal (Other academic)
  • 45.
    Rinne, S.
    et al.
    Uppsala Univ, Uppsala, Sweden..
    Leitao, Charles Dahlsson
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Mitran, B.
    Uppsala Univ, Uppsala, Sweden..
    Tolmachev, V.
    Uppsala Univ, Uppsala, Sweden..
    Ståhl, Stefan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Orlova, A.
    Uppsala Univ, Uppsala, Sweden..
    Optimizing affibody-mediated PET imaging of HER3 expression using long-lived radiocobalt for the next day PET image2019In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no SUPPL 1, p. S436-S436Article in journal (Other academic)
  • 46.
    Rinne, S.
    et al.
    Uppsala Univ, Uppsala, Sweden..
    Mitran, B.
    Uppsala Univ, Uppsala, Sweden..
    Vorobyeva, A.
    Uppsala Univ, Uppsala, Sweden..
    Leitao, Charles Dahlsson
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Andersson, K.
    KTH.
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Tolmachev, V.
    Uppsala Univ, Uppsala, Sweden..
    Orlova, A.
    Uppsala Univ, Uppsala, Sweden..
    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, p. S109-S109Article in journal (Other academic)
  • 47. Rosestedt, M.
    et al.
    Andersson, Ken
    KTH, School of Biotechnology (BIO), Protein Technology.
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    Mitran, B.
    Tolmachev, V.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Orlova, A.
    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, p. S310-S310Article in journal (Other academic)
  • 48. Rosestedt, M.
    et al.
    Mitran, B.
    Andersson, K. G.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Löfblom, J.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Ståhl, S.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    Orlova, A.
    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)
  • 49.
    Rosik, Daniel
    et al.
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Orlova, Anna
    Malmberg, Jennie
    Altai, Mohamed
    Varasteh, Zohreh
    Sandström, Mattias
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Tolmachev, Vladimir
    Direct comparison of In-111-labelled two-helix and three-helix Affibody molecules for in vivo molecular imaging2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, no 4, p. 693-702Article in journal (Refereed)
    Abstract [en]

    Radiolabelled Affibody molecules have demonstrated a potential for visualization of tumour-associated molecular targets. Affibody molecules (7 kDa) are composed of three alpha-helices. Recently, a smaller two-helix variant of Affibody molecules (5.1 kDa) was developed. The aim of this study was to compare two- and three-helix HER2-targeting Affibody molecules directly in vivo. The three-helix Affibody molecule ABY-002 and the two-helix Affibody molecule PEP09239 were labelled with In-111 at the N-termini via DOTA chelator. Tumour-targeting properties were directly compared at 1 and 4 h after injection in mice bearing SKOV-3 xenografts with high HER2 expression and LS174T xenografts with low HER2 expression. The dissociation constants (K (D)) for HER2 binding were 78 pM for the three-helix Affibody molecule and 2.1 nM for the two-helix Affibody molecule. In-111-PEP09239 cleared more rapidly from the blood. In xenografts with high HER2 expression, the uptake of In-111-ABY-002 was significantly higher than that of In-111-PEP09239. The tumour-to-blood ratio was higher for In-111-PEP09239 at 4 h after injection, while there was no significant difference in other tumour-to-organ ratios. The tumour uptake of In-111-ABY-002 was eightfold higher than that of In-111-PEP09239 in xenografts with low expression. Tumour-to-blood ratios were equal in this case, but other tumour-to-organ ratios were appreciably higher for the three-helix variant. For tumours with high HER2 expression, two-helix HER2-targeting Affibody molecules can provide higher tumour-to-blood ratio at the cost of lower tumour uptake. In the case of low expression, both tumour uptake and tumour-to-organ ratios are appreciably higher for three-helix than for two-helix HER2-targeting Affibody molecules.

  • 50. Steffen, A.C
    et al.
    Orlova, A
    Wikman, Maria
    Nilsson, F.Y
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Adams, G.P
    Tolmachev, V
    Carlsson, J
    Affibody mediated tumor targeting of HER-2 expressing xenografts in mice2006In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 33, no 6, p. 631-638Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Targeted delivery of radionuclides for diagnostic and therapeutic applications has until recently largely been limited to receptor ligands, antibodies and antibody-derived molecules. Here, we present a new type of molecule, a 15-kDa bivalent affibody called (Z(HER2:4))(2), with potential for such applications. The (Z(HER2:4))(2) affibody showed high apparent affinity (K (D)=3 nM) towards the oncogene product HER-2 (also called p185/neu or c-erbB-2), which is often overexpressed in breast and ovarian cancers. The purpose of this study was to investigate the in vivo properties of the new targeting agent.

    METHODS:

    The biodistribution and tumour uptake of the radioiodinated (Z(HER2:4))(2) affibody was studied in nude mice carrying tumours from xenografted HER-2 overexpressing SKOV-3 cells.

    RESULTS:

    The radioiodinated (Z(HER2:4))(2) affibody was primarily excreted through the kidneys, and significant amounts of radioactivity were specifically targeted to the tumours. The blood-borne radioactivity was, at all times, mainly in the macromolecular fraction. A tumour-to-blood ratio of about 10:1 was obtained 8 h post injection, and the tumours could be easily visualised with a gamma camera at this time point.

    CONCLUSION:

    The results indicate that the (Z(HER2:4))(2) affibody is an interesting candidate for applications in nuclear medicine, such as radionuclide-based tumour imaging and therapy.

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