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EJNMMI Research
Published in: EJNMMI Research 1/2020

01-12-2020 | Colchicine | Original research

On the prevention of kidney uptake of radiolabeled DARPins

Authors: Mohamed Altai, Javad Garousi, Sara S. Rinne, Alexey Schulga, Sergey Deyev, Anzhelika Vorobyeva

Published in: EJNMMI Research | Issue 1/2020

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Abstract

Background

Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins (14–18 kDa) that demonstrated promising tumor-targeting properties in preclinical studies. However, high renal accumulation of activity for DARPins labeled with residualizing labels is a limitation for targeted radionuclide therapy. A better understanding of the mechanisms behind the kidney uptake of DARPins could aid the development of strategies to reduce it. In this study, we have investigated whether the renal uptake of [99mTc]Tc(CO)3-G3 DARPin could be reduced by administration of compounds that act on various parts of the reabsorption system in the kidney.

Results

Co-injection of lysine or Gelofusine was not effective for the reduction of kidney uptake of [99mTc]Tc(CO)3-G3. Administration of sodium maleate before the injection of [99mTc]Tc(CO)3-G3 reduced the kidney-associated activity by 60.4 ± 10.3%, while administration of fructose reduced it by 46.9 ± 7.6% compared with the control. The decrease in the kidney uptake provided by sodium maleate was also observed for [99mTc]Tc(CO)3-9_29 DARPin. Preinjection of colchicine, probenecid, mannitol, or furosemide had no effect on the kidney uptake of [99mTc]Tc(CO)3-G3. Kidney autoradiography showed mainly cortical accumulation of activity for all studied groups.

Conclusion

Common clinical strategies were not effective for the reduction of kidney uptake of [99mTc]Tc(CO)3-G3. Both fructose and maleate lower the cellular ATP level in the proximal tubule cells and their reduction of the kidney reuptake indicates the involvement of an ATP-driven uptake mechanism. The decrease provided by maleate for both G3 and 9_29 DARPins indicates that their uptake proceeds through a mechanism independent of DARPin structure and binding site composition.
Literature
1.
Krasniqi A, D’Huyvetter M, Devoogdt N, Frejd FY, Sörensen J, Orlova A, Keyaerts M, Tolmachev V. Same-day imaging using small proteins: clinical experience and translational prospects in oncology. J Nucl Med. 2018;59:885–91.PubMedCrossRef
2.
Feldwisch J, Tolmachev V. Engineering of affibody molecules for therapy and diagnostics. Methods Mol Biol. 2012;899:103–26.PubMedCrossRef
3.
Lindbo S, Garousi J, Mitran B, Altai M, Buijs J, Orlova A, Hober S, Tolmachev V. Radionuclide tumor targeting using ADAPT scaffold proteins: aspects of label positioning and rResidualizing properties of the label. J Nucl Med. 2018;59:93–9.PubMedCrossRef
4.
Goldstein R, Sosabowski J, Livanos M, Leyton J, Vigor K, Bhavsar G, Nagy-Davidescu G, Rashid M, Miranda E, Yeung J, Tolner B, Plückthun A, Mather S, Meyer T, Chester K. Development of the designed ankyrin repeat protein (DARPin) G3 for HER2 molecular imaging. Eur J Nucl Med Mol Imaging. 2015;42:288–301.PubMedCrossRef
5.
Vorobyeva A, Bragina O, Altai M, Mitran B, Orlova A, Shulga A, Proshkina G, Chernov V, Tolmachev V, Deyev S. Comparative evaluation of radioiodine and technetium-labeled DARPin 9_29 for radionuclide molecular imaging of HER2 expression in malignant tumors. Contrast Media Mol Imaging. 2018;2018:6930425.PubMedPubMedCentralCrossRef
6.
Deyev S, Vorobyeva A, Schulga A, Proshkina G, Güler R, Löfblom J, 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 properties. Mol Pharm. 2019;3:995–1008.CrossRef
7.
Vorobyeva A, Schulga A, Konovalova E, Güler R, Löfblom J, Sandström M, Garousi J, Chernov V, Bragina O, Orlova A, Tolmachev V, Deyev SM. Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3. Sci Rep. 2019;9:9405.PubMedPubMedCentralCrossRef
8.
Vorobyeva A, Schulga A, Konovalova E, Güler R, Mitran B, Garousi J, Rinne SS, Löfblom J, Orlova A, Deyev S, Tolmachev V. Comparison of tumor-targeting properties of directly and indirectly radioiodinated designed ankyrin repeat protein (DARPin) G3 variants for molecular imaging of HER2. Int J Oncol. 2019;4:1209–20.
9.
Vorobyeva A, Schulga A, Rinne SS, Günther T, Orlova A, Deyev S, Tolmachev V. Indirect radioiodination of DARPin G3 using N-succinimidyl-para-iodobenzoate improves the contrast of HER2 molecular imaging. Int J Mol Sci. 2019;20:E3047.PubMedCrossRef
10.
Binz HK, Stumpp MT, Forrer P, Amstutz P, Pluckthun A. Designing repeat proteins: well-expressed, soluble and stable proteins from combinatorial libraries of consensus ankyrin repeat proteins. J Mol Biol. 2003;332:489–503.PubMedCrossRef
11.
Tolmachev V. Influence of labelling method on targeting properties. In: Stigbrand T, Carlsson J, Adams GP, editors. Targeted radionuclide tumor therapy. Netherlands: Springer; 2008. p. 158–64.
12.
Ekblad T, Tran T, Orlova A, Widström C, Feldwisch J, Abrahmsén L, Wennborg A, Karlström AE, Tolmachev V. Development and preclinical characterisation of 99mTc-labelled affibody molecules with reduced renal uptake. Eur J Nucl Med Mol Imaging. 2008;35:2245–55.PubMedCrossRef
13.
Tran T, Ekblad T, Orlova A, Sandström M, Feldwisch J, Wennborg A, Abrahmsén L, Tolmachev V, Eriksson KA. Effects of lysine-containing mercaptoacetyl-based chelators on the biodistribution of 99mTc-labeled anti-HER2 affibody molecules. Bioconjug Chem. 2008;19:2568–76.PubMedCrossRef
14.
Orlova A, Tran TA, Ekblad T, Karlström AE, Tolmachev V. (186) Re-maSGS-Z (HER2:342), a potential Affibody conjugate for systemic therapy of HER2-expressing tumours. Eur J Nucl Med Mol Imaging. 2010;37:260–9.PubMedCrossRef
15.
Ahlgren S, Wållberg H, Tran TA, Widström C, Hjertman M, Abrahmsén L, Berndorff D, Dinkelborg LM, Cyr JE, Feldwisch J, Orlova A, Tolmachev V. Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine. J Nucl Med. 2009;50:781–9.PubMedCrossRef
16.
Wållberg H, Orlova A, Altai M, Hosseinimehr SJ, Widström C, Malmberg J, Ståhl S, Tolmachev V. Molecular design and optimization of 99mTc-labeled recombinant affibody molecules improves their biodistribution and imaging properties. J Nucl Med. 2011;52:461–9.PubMedCrossRef
17.
Altai M, Honarvar H, Wållberg H, Strand J, Varasteh Z, Rosestedt M, Orlova A, Dunås F, Sandström M, Löfblom J, Tolmachev V, Ståhl S. Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with (188) Re. Eur J Med Chem. 2014;87:519–28.PubMedCrossRef
18.
Tolmachev V, Orlova A, Pehrson R, Galli J, Baastrup B, Andersson K, Sandström M, Rosik D, Carlsson J, Lundqvist H, Wennborg A, Nilsson FY. Radionuclide therapy of HER2-positive microxenografts using a 177Lulabeled HER2-specific Affibody molecule. Cancer Res. 2007;67:2773–82.PubMedCrossRef
19.
Orlova A, Jonsson A, Rosik D, Lundqvist H, Lindborg M, Abrahmsen L, Ekblad C, Frejd FY, Tolmachev V. Site-specific radiometal labeling and improved biodistribution using ABY-027, a novel HER2-targeting affibody molecule-albumin-binding domain fusion protein. J Nucl Med. 2013;54:961–8.PubMedCrossRef
20.
21.
Liu G, Mang’era K, Liu N, Gupta S, Rusckowski M, Hnatowich DJ. Tumor pretargeting in mice using 99mTc-labeled morpholino, a DNA analog. J Nucl Med. 2002;43:384–91.PubMed
22.
Westerlund K, Altai M, Mitran B, Konijnenberg M, Oroujeni M, Atterby C, de Jong M, Orlova A, Mattsson J, Micke P, Karlström AE, Tolmachev V. Radionuclide therapy of HER2-expressing human xenografts using affibody-based peptide nucleic acid-mediated pretargeting: in vivo proof of principle. J Nucl Med. 2018;59:1092–8.PubMedCrossRef
23.
Rossin R, Verkerk PR, van den Bosch SM, Vulders RC, Verel I, Lub J, Robillard MS. In vivo chemistry for pretargeted tumor imaging in live mice. Angew Chem Int Ed Eng. 2010;49:3375–8.CrossRef
24.
Altai M, Perols A, Tsourma M, Mitran B, Honarvar H, Robillard M, Rossin R, ten Hoeve W, Lubberink M, Orlova A, Karlström AE, Tolmachev V. Feasibility of affibody-based bioorthogonal chemistry—mediated radionuclide pretargeting. J Nucl Med. 2016;57:431–6.PubMedCrossRef
25.
26.
Forero A, Weiden PL, Vose JM, Knox SJ, LoBuglio AF, Hankins J, Goris ML, Picozzi VJ, Axworthy DB, Breitz HB, Sims RB, Ghalie RG, Shen S, Meredith RF. Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma. Blood. 2004;104:227–36.PubMedCrossRef
27.
Bodet-Milin C, Faivre-Chauvet A, Carlier T, Rauscher A, Bourgeois M, Cerato E, Rohmer V, Couturier O, Drui D, Goldenberg DM, Sharkey RM, Barbet J, Kraeber-Bodere. Immuno-PET using anticarcinoembryonic antigen bispecific antibody and 68Ga-labeled peptide in metastatic medullary thyroid carcinoma: clinical optimization of the pretargeting parameters in a first-in-human trial. J Nucl Med. 2016;57:1505–11.PubMedCrossRef
28.
Behr TM, Goldenberg DM, Becker W. Reducing the renal uptake of radiolabeled antibody fragments and peptides for diagnosis and therapy: present status, future prospects and limitations. Eur J Nucl Med. 1998;25:201–12.PubMedCrossRef
29.
Sörensen J, Sandberg D, Sandström M, Wennborg A, Feldwisch J, Tolmachev V, Åström G, Lubberink M, Garske-Román U, Carlsson J, Lindman H. First-in-human molecular imaging of HER2 expression in breast cancer metastases using the 111In-ABY-025 affibody molecule. J Nucl Med. 2014;55:730–5.PubMedCrossRef
30.
Rolleman EJ, Valkema R, de Jong M, Kooij PP, Krenning EP. Safe and effective inhibition of renal uptake of radiolabeled octreotide by a combination of lysine and arginine. Eur J Nucl Med Mol Imaging. 2003;30:9–15.PubMedCrossRef
31.
Vegt E, Wetzels JF, Russel FG, Masereeuw R, Boerman OC, van Eerd JE, Corstens FH, Oyen WJ. Renal uptake of radiolabeled octreotide in human subjects is efficiently inhibited by succinylated gelatin. J Nucl Med. 2006;47:432–6.PubMed
32.
Christensen EI, Birn H. Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol. 2002;3:256–66.PubMedCrossRef
33.
Altai M, Varasteh Z, Andersson K, Eek A, Boerman O, Orlova A. In vivo and in vitro studies on renal uptake of radiolabeled affibody molecules for imaging of HER2 expression in tumors. Cancer Biother Radiopharm. 2013;28:187–95.PubMedCrossRef
34.
Gainkam LO, Caveliers V, Devoogdt N. Localization, mechanism and reduction of renal retention of technetium-99m labeled epidermal growth factor receptor-specific nanobody in mice. Contrast Media Mol Imaging. 2011;6:85–92.PubMedCrossRef
35.
Rolleman EJ, Krenning EP, Van Gameren A, Bernard BF, De Jong M. Uptake of [111In-DTPA0] octreotide in the rat kidney is inhibited by colchicine and not by fructose. J Nucl Med. 2004;45:709–13.PubMed
36.
Melis M, Krenning EP, Bernard BF, Barone R, Visser TJ, de Jong M. Localisation and mechanism of renal retention of radiolabelled somatostatin analogues. Eur J Nucl Med Mol Imaging. 2005;32:1136–43.PubMedCrossRef
37.
Stahl AR, Wagner B, Poethko T, Perutka M, Wester HJ, Essler M, Heemann U, Schwaiger M, Lutz J. Renal accumulation of [111In] DOTATOC in rats: influence of inhibitors of the organic ion transport and diuretics. Eur J Nucl Med Mol Imaging. 2007;34:2129–34.PubMedCrossRef
38.
Jost C, Schilling J, Tamaskovic R, Schwill M, Honegger A, Plückthun A. Structural basis for eliciting a cytotoxic effect in HER2-overexpressing cancer cells via binding to the extracellular domain of HER2. Structure. 2013;21:1979–91.PubMedCrossRef
39.
Christensen EI, Birn H, Verroust P, Moestrup SK. Membrane receptors for endocytosis in the renal proximal tubule. Int Rev Cytol. 1998;180:237–84.PubMedCrossRef
40.
Nielsen S. Endocytosis in proximal tubule cells involves a two-phase membrane- recycling pathway. Am J Phys. 1993;264:C823–35.CrossRef
41.
Engfeldt T, Orlova A, Tran T, Bruskin A, Widström KAE, Tolmachev V. Imaging of HER2-expressing tumours using a synthetic affibody molecule containing the 99mTc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence. Eur J Nucl Med Mol Imaging. 2007;34:722–33.PubMedCrossRef
42.
Tran TA, Rosik D, Abrahmsén L, Sandström M, Sjöberg A, Wållberg H, Ahlgren S, Orlova A, Tolmachev V. Design, synthesis and biological evaluation of a multifunctional HER2-specific Affibody molecule for molecular imaging. Eur J Nucl Med Mol Imaging. 2009;36:1864–73.PubMedCrossRef
43.
Christensen EI, Verroust PJ. Megalin and cubilin, role in proximal tubule function and during development. Pediatr Nephrol. 2002;17:993–9.PubMedCrossRef
44.
Rogulski J, Pacanis A. Effects of maleate on CoA metabolism in rat kidney. Curr Probl Clin Biochem. 1977;8:406–15.PubMed
45.
Cho J, Galaske RG, Arbesman H, Van Liew JB. Renal albumin reabsorption in normal and sodium maleate-treated rats. Renal Physiol. 1985;5:8–18.
46.
Harrison HE, Harrison HC. Experimental production of renal glycosuria, phosphaturia and aminoaciduria by injection of maleic acid. Science. 1954;120:606–8.PubMedCrossRef
47.
Kramer HJ, Gonick HC. Experimental Fanconi syndrome. I. Effect of maleic acid on renal cortical NaK-ATPase activity and ATP levels. J Lab Clin Med. 1970;76:799–808.PubMed
48.
Burch HB, Choi S, Dence CN, Alvey TR, Cole BR, Lowry OH. Metabolic effects of large fructose loads in different parts of the rat nephron. J Biol Chem. 1980;255:8239–44.PubMed
Metadata
Title
On the prevention of kidney uptake of radiolabeled DARPins
Authors
Mohamed Altai
Javad Garousi
Sara S. Rinne
Alexey Schulga
Sergey Deyev
Anzhelika Vorobyeva
Publication date
01-12-2020
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2020
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-020-0599-1

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