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  • 1.
    Altai, Mohamed
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden.;Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
    Leitao, Charles Dahlsson
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Rinne, Sara S.
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
    Vorobyeva, Anzhelika
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Atterby, Christina
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Ståhl, Stefan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, S-75237 Uppsala, Sweden..
    Influence of Molecular Design on the Targeting Properties of ABD-Fused Mono- and Bi-Valent Anti-HER3 Affibody Therapeutic Constructs2018In: CELLS, ISSN 2073-4409, Vol. 7, no 10, article id 164Article in journal (Refereed)
    Abstract [en]

    Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (ABD 035) included for the extension of half-life in circulation. The 3A3 fusion protein (19.7 kDa) was shown to delay tumour growth in mice bearing HER3-expressing xenografts and was equipotent to the mAb seribantumab. Here, we have designed and explored a series of novel formats of anti-HER3 affibody molecules fused to the ABD in different orientations. All constructs inhibited heregulin-induced phosphorylation in HER3-expressing BxPC-3 and DU-145 cell lines. Biodistribution studies demonstrated extended the half-life of all ABD-fused constructs, although at different levels. The capacity of our ABD-fused proteins to accumulate in HER3-expressing tumours was demonstrated in nude mice bearing BxPC-3 xenografts. Formats where the ABD was located on the C-terminus of affibody binding domains (3A, 33A, and 3A3) provided the best tumour targeting properties in vivo. Further development of these promising candidates for treatment of HER3-overexpressing tumours is therefore justified.

  • 2.
    Ding, Haozhong
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Altai, Mohamed
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Rinne, Sara S.
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
    Vorobyeva, Anzhelika
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Gräslund, Torbjörn
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, S-75123 Uppsala, Sweden..
    Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody-DM1 Drug Conjugates2019In: Cancers, ISSN 2072-6694, Vol. 11, no 8, article id 1168Article in journal (Refereed)
    Abstract [en]

    Affibody molecules are small affinity-engineered scaffold proteins which can be engineered to bind to desired targets. The therapeutic potential of using an affibody molecule targeting HER2, fused to an albumin-binding domain (ABD) and conjugated with the cytotoxic maytansine derivate MC-DM1 (AffiDC), has been validated. Biodistribution studies in mice revealed an elevated hepatic uptake of the AffiDC, but histopathological examination of livers showed no major signs of toxicity. However, previous clinical experience with antibody drug conjugates have revealed a moderateto high-grade hepatotoxicity in treated patients, which merits efforts to also minimize hepatic uptake of the AffiDCs. In this study, the aim was to reduce the hepatic uptake of AffiDCs and optimize their in vivo targeting properties. We have investigated if incorporation of hydrophilic glutamate-based spacers adjacent to MC-DM1 in the AffiDC, (Z(HER2:2891))(2) -ABD-MC-DM1, would counteract the hydrophobic nature of MC-DM1 and, hence, reduce hepatic uptake. Two new AffiDCs including either a triglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-3-MC-DM1, or a hexaglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-6-MC-DM1 next to the site of MC-DM1 conjugation were designed. We radiolabeled the hydrophilized AffiDCs and compared them, both in vitro and in vivo, with the previously investigated (Z(HER2:2891))(2)-ABD-MC-DM1 drug conjugate containing no glutamate spacer. All three AffiDCs demonstrated specific binding to HER2 and comparable in vitro cytotoxicity. A comparative biodistribution study of the three radiolabeled AffiDCs showed that the addition of glutamates reduced drug accumulation in the liver while preserving the tumor uptake. These results confirmed the relation between DM1 hydrophobicity and liver accumulation. We believe that the drug development approach described here may also be useful for other affinity protein-based drug conjugates to further improve their in vivo properties and facilitate their clinical translatability.

  • 3. Mitran, Bogdan
    et al.
    Andersson, Ken Gösta
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH).
    Lindstrom, Elin
    Garousi, Javad
    Rosestedt, Maria
    Tolmachev, Vladimir
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Orlova, Anna
    Löfblom, John
    KTH, School of Engineering Sciences (SCI). KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    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.

  • 4.
    Oroujeni, Maryam
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75181 Uppsala, Sweden..
    Andersson, Ken G.
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75181 Uppsala, Sweden..
    Steinhardt, Xenia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Altai, Mohamed
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75181 Uppsala, Sweden..
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Mitran, Bogdan
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Vorobyeva, Anzhelika
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75181 Uppsala, Sweden..
    Garousi, Javad
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75181 Uppsala, Sweden..
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75181 Uppsala, Sweden..
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Influence of composition of cysteine-containing peptide-based chelators on biodistribution of Tc-99m-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.

  • 5.
    Oroujeni, Maryam
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Garousi, Javad
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Andersson, Ken G.
    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, Bogdan
    Uppsala Univ, Dept Med Chem, SE-75123 Uppsala, Sweden..
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, SE-75123 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, SE-75003 Uppsala, Sweden..
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Preclinical Evaluation of [Ga-68]Ga-DFO-ZEGFR:2377: A Promising Affibody-Based Probe for Noninvasive PET Imaging of EGFR Expression in Tumors2018In: CELLS, 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.

  • 6.
    Rinne, Sara S.
    et al.
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Leitao, Charles Dahlsson
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Mitran, Bogdan
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Bass, Tarek
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Andersson, Ken G.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    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.
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, Uppsala, Sweden..
    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.

  • 7.
    Rinne, Sara S.
    et al.
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
    Xu, Tianqi
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Leitao, Charles Dahlsson
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    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.
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, S-75123 Uppsala, Sweden.;Natl Res Tomsk Polytech Univ, Ctr Oncotheranost, Tomsk 634050, Russia..
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden.;Natl Res Tomsk Polytech Univ, Ctr Oncotheranost, Tomsk 634050, Russia..
    Vorobyeva, Anzhelika
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden.;Natl Res Tomsk Polytech Univ, Ctr Oncotheranost, Tomsk 634050, Russia..
    Influence of Residualizing Properties of the Radiolabel on Radionuclide Molecular Imaging of HER3 Using Affibody Molecules2020In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 21, no 4, article id 1312Article in journal (Refereed)
    Abstract [en]

    Human epidermal growth factor receptor type 3 (HER3) is an emerging therapeutic target in several malignancies. To select potential responders to HER3-targeted therapy, radionuclide molecular imaging of HER3 expression using affibody molecules could be performed. Due to physiological expression of HER3 in normal organs, high imaging contrast remains challenging. Due to slow internalization of affibody molecules by cancer cells, we hypothesized that labeling (HE)(3)-Z(HER3:08698)-DOTAGA affibody molecule with non-residualizing [I-125]-N-succinimidyl-4-iodobenzoate (PIB) label would improve the tumor-to-normal organs ratios compared to previously reported residualizing radiometal labels. The [I-125]I-PIB-(HE)(3)-Z(HER3:08698)-DOTAGA was compared side-by-side with [In-111]In-(HE)(3)-Z(HER3:08698)-DOTAGA. Both conjugates demonstrated specific high-affinity binding to HER3-expressing BxPC-3 and DU145 cancer cells. Biodistribution in mice bearing BxPC-3 xenografts at 4 and 24h pi showed faster clearance of the [I-125]I-PIB label compared to the indium-111 label from most tissues, except blood. This resulted in higher tumor-to-organ ratios in HER3-expressing organs for [I-125]I-PIB-(HE)(3)-Z(HER3:08698)-DOTAGA at 4 h, providing the tumor-to-liver ratio of 2.4 +/- 0.3. The tumor uptake of both conjugates was specific, however, it was lower for the [I-125]I-PIB label. In conclusion, the use of non-residualizing [I-125]I-PIB label for HER3-targeting affibody molecule provided higher tumor-to-liver ratio than the indium-111 label, however, further improvement in tumor uptake and retention is needed.

  • 8.
    Rosestedt, Maria
    et al.
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Andersson, Ken G.
    Rinne, Sara S.
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Leitao, Charles Dahlsson
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Mitran, Bogdan
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Vorobyeva, Anzhelika
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, Uppsala, Sweden..
    Improved contrast of affibody-mediated imaging of HER3 expression in mouse xenograft model through co-injection of a trivalent affibody for in vivo blocking of hepatic uptake2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6779Article in journal (Refereed)
    Abstract [en]

    Human epidermal growth factor receptor type 3 (HER3) plays a crucial role in the progression of many cancer types. In vivo radionuclide imaging could be a reliable method for repetitive detection of HER3-expression in tumors. The main challenge of HER3-imaging is the low expression in tumors together with endogenous receptor expression in normal tissues, particularly the liver. A HER3-targeting affibody molecule labeled with radiocobalt via a NOTA chelator [Co-57]Co-NOTA-Z(08699) has demonstrated the most favorable biodistribution profile with the lowest unspecific hepatic uptake and high activity uptake in tumors. We hypothesized that specific uptake of labeled affibody monomer might be selectively blocked in the liver but not in tumors by a co-injection of non-labeled corresponding trivalent affibody (Z(08699))(3). Biodistribution of [Co-57]Co-NOTA-Z(08699) and [In-111]ln-DOTA-(Z(08699))(3) was studied in BxPC-3 xenografted mice. [Co-57]Co-NOTA-Z(08699) was co-injected with unlabeled trivalent affibody DOTA-(Z(08699))(3) at different monomer:trimer molar ratios. HER3-expression in xenografts was imaged using [Co-57]Co-NOTA-Z(08699) and [Co-57]Co-NOTA-Z(08699): DOTA-(Z(08699))(3). Hepatic activity uptake of [Co-57] Co-NOTA-Z(08699): DOTA-(Z(08699))(3) decreased with increasing monomer:trimer molar ratio. The tumor activity uptake and tumor-to-liver ratios were the highest for the 1:3 ratio. SPECT/CT images confirmed the biodistribution data. Imaging of HER3 expression can be improved by co-injection of a radiolabeled monomeric affi body-based imaging probe together with a trivalent affibody.

  • 9.
    Tolmachev, Vladimir
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Gronroos, Tove J.
    Univ Turku, Turku PET Ctr, Turku, Finland.;Univ Turku, MediCity Res Lab, Turku, Finland.;Turku Univ Hosp, Dept Oncol & Radiotherapy, Turku, Finland..
    Yim, Cheng-Bin
    Univ Turku, Turku PET Ctr, Turku, Finland.;Abo Akad Univ, Turku PET Ctr, Turku, Finland..
    Garousi, Javad
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Yue, Ying
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Grimm, Sebastian
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Rajander, Johan
    Abo Akad Univ, Turku PET Ctr, Turku, Finland..
    Perols, Anna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Haaparanta-Solin, Merja
    Univ Turku, Turku PET Ctr, Turku, Finland.;Univ Turku, Dept Chem, Turku, Finland..
    Solin, Olof
    Univ Turku, Turku PET Ctr, Turku, Finland.;Abo Akad Univ, Turku PET Ctr, Turku, Finland.;Univ Turku, Dept Chem, Turku, Finland..
    Ferdani, Riccardo
    Washington Univ, St Louis, MO USA..
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Anderson, Carolyn J.
    Univ Pittsburgh, Dept Med, Pittsburgh, PA 15203 USA.;Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15203 USA.;Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15203 USA.;Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15203 USA..
    Karlström, Amelie Eriksson
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Molecular design of radiocopper-labelled Affibody molecules2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 6542Article in journal (Refereed)
    Abstract [en]

    The use of long-lived positron emitters Cu-64 or Cu-61 for labelling of Affibody molecules may improve breast cancer patients' stratification for HER-targeted therapy. Previous animal studies have shown that the use of triaza chelators for Cu-64 labelling of synthetic Affibody molecules is suboptimal. In this study, we tested a hypothesis that the use of cross-bridged chelator, CB-TE2A, in combination with Gly-Glu-Glu-Glu spacer for labelling of Affibody molecules with radiocopper would improve imaging contrast. CB-TE2A was coupled to the N-terminus of synthetic Affibody molecules extended either with a glycine (designation CB-TE2A-G-ZHER2:342) or Gly-Glu-Glu-Glu spacer (CB-TE2A-GEEE-ZHER2:342). Biodistribution and targeting properties of Cu-64-CB-TE2A-G-ZHER2:342 and Cu-64-CB-TE2A-GEEE-ZHER2:342 were compared in tumor-bearing mice with the properties of Cu-64-NODAGA-ZHER2:S1, which had the best targeting properties in the previous study. Cu-64-CB-TE2A-GEEE-ZHER2:342 provided appreciably lower uptake in normal tissues and higher tumor-to-organ ratios than Cu-64-CB-TE2A-GZHER2:342 and Cu-64-NODAGA-ZHER2:S1. The most pronounced was a several-fold difference in the hepatic uptake. At the optimal time point, 6 h after injection, the tumor uptake of Cu-64-CB-TE2A-GEEE-ZHER2: 342 was 16 +/- 6% ID/g and tumor-to-blood ratio was 181 +/- 52. In conclusion, a combination of the cross-bridged CB-TE2A chelator and Gly-Glu-Glu-Glu spacer is preferable for radiocopper labelling of Affibody molecules and, possibly, other scaffold proteins having high renal re-absorption.

  • 10.
    von Witting, Emma
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Garousi, Javad
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Lindbo, Sarah
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Vorobyeva, Anzhelika
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Altai, Mohamed
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Oroujeni, Maryam
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Mitran, Bogdan
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Orlova, Anna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Hober, Sophia
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Selection of the optimal macrocyclic chelators for labeling with In-111 and Ga-68 improves contrast of HER2 imaging using engineered scaffold protein ADAPT62019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 140, p. 109-120Article in journal (Refereed)
    Abstract [en]

    Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with In-111 for SPECT and Ga-68 for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-toorgan ratios. Hence, it was concluded that the best variant for SPECT imaging is In-111-(HE)(3)DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is Ga-68-(HE)(3)DANS-ADAPT6-GSSC-NODAGA.

  • 11.
    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.

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