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Influence of the N-Terminal Composition on Targeting Properties of Radiometal-Labeled Anti-HER2 Scaffold Protein ADAPT6
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. (Vladimir Tolmachev)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. (Vladimir Tolmachev)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. (Vladimir Tolmachev)
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2016 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 27, no 11, 2678-2688 p.Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
2016. Vol. 27, no 11, 2678-2688 p.
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-312075DOI: 10.1021/acs.bioconjchem.6b00465ISI: 000388430700011PubMedID: 27740752OAI: oai:DiVA.org:uu-312075DiVA: diva2:1062154
Funder
Swedish Cancer Society, CAN 2015/350Swedish Research Council, 2015-02353Swedish Research Council, 621-2012-5088
Available from: 2017-01-04 Created: 2017-01-04 Last updated: 2017-01-12Bibliographically approved

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Garousi, JavadHonarvar, HadisBogdan, MitranAltai, MohamedOrlova, AnnaTolmachev, Vladimir
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