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  • 1. Deyev, S.
    et al.
    Vorobyeva, A.
    Schulga, A.
    Proshkina, G.
    Güler, Rezan
    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.
    Mitran, B.
    Garousi, J.
    Altai, M.
    Buijs, J.
    Chernov, V.
    Orlova, A.
    Tolmachev, V.
    Comparative Evaluation of Two DARPin Variants: Effect of Affinity, Size, and Label on Tumor Targeting Properties2019In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 16, no 3, p. 995-1008Article in journal (Refereed)
    Abstract [en]

    Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins that can be selected for binding to desirable molecular targets. High affinity and small size of DARPins render them promising probes for radionuclide molecular imaging. However, detailed knowledge on many factors influencing their imaging properties is still lacking. We have evaluated two human epidermal growth factor 2 (HER2)-specific DARPins with different size and binding properties. DARPins 9-29-H 6 and G3-H 6 were radiolabeled with iodine-125 and tricarbonyl technetium-99m and evaluated in vitro. A side-by-side comparison of biodistribution and tumor targeting was performed. HER2-specific tumor accumulation of G3-H 6 was demonstrated. A combination of smaller size and higher affinity resulted in a higher tumor uptake of G3-H 6 in comparison to 9-29-H 6 . Technetium-99m labeled G3-H 6 demonstrated a better biodistribution profile than 9-29-H 6 , with several-fold lower uptake in liver. Radioiodinated G3-H 6 showed the best tumor-to-organ ratios. The combined effect of affinity, molecular weight, scaffold composition, and nonresidualizing properties of iodine label provided radioiodinated G3-H 6 with high clinical potential for imaging of HER2.

  • 2.
    Fleetwood, Filippa
    et al.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Güler, Rezan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Gordon, Emma
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Claesson-Welsh, Lena
    Löfblom, John
    Novel affinity binders for neutralization of vascular endothelial growth factor (VEGF) signaling2016In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 73, no 8, p. 1671-1683Article in journal (Refereed)
    Abstract [en]

    Angiogenesis denotes the formation of new blood vessels from pre-existing vasculature. Progression of diseases such as cancer and several ophthalmological disorders may be promoted by excess angiogenesis. Novel therapeutics to inhibit angiogenesis and diagnostic tools for monitoring angiogenesis during therapy, hold great potential for improving treatment of such diseases. We have previously generated so-called biparatopic Affibody constructs with high affinity for the vascular endothelial growth factor receptor-2 (VEGFR2), which recognize two non-overlapping epitopes in the ligand-binding site on the receptor. Affibody molecules have previously been demonstrated suitable for imaging purposes. Their small size also makes them attractive for applications where an alternative route of administration is beneficial, such as topical delivery using eye drops. In this study, we show that decreasing linker length between the two Affibody domains resulted in even slower dissociation from the receptor. The new variants of the biparatopic Affibody bound to VEGFR2-expressing cells, blocked VEGFA binding, and inhibited VEGFA-induced signaling of VEGFR2 over expressing cells. Moreover, the biparatopic Affibody inhibited sprout formation of endothelial cells in an in vitro angiogenesis assay with similar potency as the bivalent monoclonal antibody ramucirumab. This study demonstrates that the biparatopic Affibody constructs show promise for future therapeutic as well as in vivo imaging applications.

  • 3.
    Güler, Rezan
    et al.
    KTH, School of Computer Science and Communication (CSC), Computer Vision and Active Perception, CVAP. KTH, School of Computer Science and Communication (CSC), Centres, Centre for Autonomous Systems, CAS. KTH, School of Biotechnology (BIO), Protein Technology.
    Pauwels, Karl
    KTH, School of Computer Science and Communication (CSC), Computer Vision and Active Perception, CVAP. KTH, School of Computer Science and Communication (CSC), Centres, Centre for Autonomous Systems, CAS.
    Pieropan, Alessandro
    KTH, School of Computer Science and Communication (CSC), Computer Vision and Active Perception, CVAP. KTH, School of Computer Science and Communication (CSC), Centres, Centre for Autonomous Systems, CAS.
    Kjellström, Hedvig
    KTH, School of Computer Science and Communication (CSC), Computer Vision and Active Perception, CVAP. KTH, School of Computer Science and Communication (CSC), Centres, Centre for Autonomous Systems, CAS.
    Kragic, Danica
    KTH, School of Computer Science and Communication (CSC), Computer Vision and Active Perception, CVAP. KTH, School of Computer Science and Communication (CSC), Centres, Centre for Autonomous Systems, CAS.
    Estimating the Deformability of Elastic Materials using Optical Flow and Position-based Dynamics2015In: Humanoid Robots (Humanoids), 2015 IEEE-RAS 15th International Conference on, IEEE conference proceedings, 2015, p. 965-971Conference paper (Refereed)
    Abstract [en]

    Knowledge of the physical properties of objects is essential in a wide range of robotic manipulation scenarios. A robot may not always be aware of such properties prior to interaction. If an object is incorrectly assumed to be rigid, it may exhibit unpredictable behavior when grasped. In this paper, we use vision based observation of the behavior of an object a robot is interacting with and use it as the basis for estimation of its elastic deformability. This is estimated in a local region around the interaction point using a physics simulator. We use optical flow to estimate the parameters of a position-based dynamics simulation using meshless shape matching (MSM). MSM has been widely used in computer graphics due to its computational efficiency, which is also important for closed-loop control in robotics. In a controlled experiment we demonstrate that our method can qualitatively estimate the physical properties of objects with different degrees of deformability.

  • 4.
    Güler, Rezan
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Thatikonda, Naresh
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Ghani, Hawraa Ali
    Hedhammar, My
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Artificial VEGFR2-Specific Growth Factors Demonstrate Agonistic Effects in Both Soluble Form and When Immobilized Via Spider SilkManuscript (preprint) (Other academic)
  • 5. 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)
  • 6.
    Mitran, Bogdan
    et al.
    Uppsala Univ, Dept Med Chem, Dag Hammarskjoldsv 14C,3Tr, S-75183 Uppsala, Sweden..
    Güler, Rezan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Roche, Francis P.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Lindstrom, Elin
    Uppsala Univ, Dept Med Chem, Dag Hammarskjoldsv 14C,3Tr, S-75183 Uppsala, Sweden..
    Selvaraju, Ram Kumar
    Uppsala Univ, Dept Med Chem, Dag Hammarskjoldsv 14C,3Tr, S-75183 Uppsala, Sweden.;Uppsala Univ, Dept Med Chem, Preclin PET MRI Platform, Uppsala, Sweden..
    Fleetwood, Filippa
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Rinne, Sara S.
    Uppsala Univ, Dept Med Chem, Dag Hammarskjoldsv 14C,3Tr, S-75183 Uppsala, Sweden..
    Claesson-Welsh, Lena
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, Uppsala, Sweden..
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Ståhl, Stefan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, Dag Hammarskjoldsv 14C,3Tr, S-75183 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, Uppsala, Sweden..
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    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.

  • 7.
    Vorobyeva, A.
    et al.
    Uppsala Univ, Uppsala, Sweden..
    Schulga, A.
    Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia..
    Konovalova, E.
    Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia..
    Güler, Rezan
    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.
    Sandstrom, M.
    Uppsala Univ, Uppsala, Sweden..
    Garousi, J.
    Uppsala Univ, Uppsala, Sweden..
    Chernov, V.
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Tomsk, Russia..
    Bragina, O.
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Tomsk, Russia..
    Orlova, A.
    Uppsala Univ, Uppsala, Sweden..
    Tolmachev, V.
    Uppsala Univ, Uppsala, Sweden..
    Deyev, S. M.
    Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia.;Natl Res Nucl Univ MEPhI, Moscow, Russia..
    N-terminal position of histidine-glutamate-containing tag improves biodistribution of [Tc-99m]Tc-labeled DARPin G32019In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no SUPPL 1, p. S749-S749Article in journal (Other academic)
  • 8.
    Vorobyeva, Anzhelika
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Schulga, Alexey
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia..
    Konovalova, Elena
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia..
    Güler, Rezan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Löfblom, John
    KTH, School of Engineering Sciences (SCI). KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Sandstrom, Mattias
    Uppsala Univ, Dept Surg Sci, Nucl Med & PET, Uppsala, Sweden..
    Garousi, Javad
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Chernov, Vladimir
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Nucl Med Dept, Tomsk, Russia..
    Bragina, Olga
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Nucl Med Dept, Tomsk, Russia..
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, Uppsala, Sweden..
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Deyev, Sergey M.
    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, Inst Engn Phys Biomed PhysBio, Bionanophoton Lab, Moscow, Russia..
    Optimal composition and position of histidine-containing tags improves biodistribution of Tc-99m-labeled DARP in G32019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 9405Article in journal (Refereed)
    Abstract [en]

    Radionuclide molecular imaging of HER2 expression in disseminated cancer enables stratification of patients for HER2-targeted therapies. DARP in G3, a small (14 kDa) engineered scaffold protein, is a promising probe for imaging of HER2. We hypothesized that position (C- or N-terminus) and composition (hexahistidine or (HE)(3)) of histidine-containing tags would influence the biodistribution of [Tc-99m]Tc(CO)(3)-labeled DARP in G3. To test the hypothesis, G3 variants containing tags at N-terminus (H-6-G3 and (HE)(3)-G3) or at C-terminus (G3-H-6 and G3-(HE)(3)) were labeled with [Tc-99m]Tc(CO)(3). Labeling yield, label stability, specificity and affinity of the binding to HER2, biodistribution and tumor targeting properties of these variants were compared side-by-side. There was no substantial influence of position and composition of the tags on binding of [Tc-99m]Tc(CO)(3)-labeled variants to HER2. The specificity of HER2 targeting in vivo was confirmed. The tumor uptake in BALB/c nu/nu mice bearing SKOV3 xenografts was similar for all variants. On the opposite, there was a strong influence of the tags on uptake in normal tissues. The tumor-to-liver ratio for [Tc-99m]Tc(CO)(3)-(HE)(3)-G3 was three-fold higher compared to the hexahistidine-tag containing variants. Overall, [Tc-99m]Tc(CO)(3)-(HE)(3)-G3 variant provided the highest tumor-to-lung, tumor-to-liver, tumor-to-bone and tumor-to-muscle ratios, which should improve sensitivity of HER2 imaging in these common metastatic sites.

  • 9.
    Vorobyeva, Anzhelika
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, Dag Hammarskjolds V 20, SE-75185 Uppsala, Sweden. hulga, Alexey; Konovalova, Elena; Deyev, Sergey.
    Schulga, Alexey
    Konovalova, Elena
    Güler, Rezan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Mitran, Bogdan
    Garousi, Javad
    Rinne, Sara
    Löfblom, John
    KTH, School of Engineering Sciences (SCI).
    Orlova, Anna
    Deyev, Sergey
    Tolmachev, Vladimir
    Comparison of tumor-targeting properties of directly and indirectly radioiodinated designed ankyrin repeat protein (DARPin) G3 variants for molecular imaging of HER22019In: International Journal of Oncology, ISSN 1019-6439, Vol. 54, no 4, p. 1209-1220Article in journal (Refereed)
    Abstract [en]

    Evaluation of human epidermal growth factor receptor 2 (HER2) expression levels in breast and gastroesophageal cancer is used for the stratification of patients for HER2-targeting therapies. The use of radionuclide molecular imaging may facilitate such evaluation in a non-invasive way. Designed ankyrin repeat proteins (DARPins) are engineered scaffold proteins with high potential as probes for radionuclide molecular imaging. DARPin G3 binds with high affinity to HER2 and may be used to visualize this important therapeutic target. Studies on other engineered scaffold proteins have demonstrated that selection of the optimal labeling approach improves the sensitivity and specificity of radionuclide imaging. The present study compared two methods of labeling G3, direct and indirect radioiodination, to select an approach providing the best imaging contrast. G3-H6 was labeled with iodine-124, iodine-125 and iodine-131 using a direct method. A novel construct bearing a C-terminal cysteine, G3-GGGC, was site-specifically labeled using [125I]I-iodo-[(4-hydroxyphenyl)ethyl]maleimide (HPEM). The two radiolabeled G3 variants preserved binding specificity and high affinity to HER2-expressing cells. The specificity of tumor targeting in vivo was demonstrated. Biodistribution comparison of [131I]I-G3-H6 and [125I]I-HPEM-G3-GGGC in mice, bearing HER2-expressing SKOV3 xenografts, demonstrated an appreciable contribution of hepatobiliary excretion to the clearance of [125I]I-HPEM-G3-GGGC and a decreased tumor uptake compared to [131I]I-G3-H6. The direct label provided higher tumor-to-blood and tumor-to-organ ratios compared with the indirect label at 4 h post-injection. The feasibility of high contrast PET/CT imaging of HER2 expression in SKOV3 xenografts in mice using [124I]I-G3-H6 was demonstrated. In conclusion, direct radioiodination is the preferable approach for labeling DARPin G3 with iodine-123 and iodine-124 for clinical single photon emission computed tomography and positron emission tomography imaging.

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