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Influence of the N-Terminal Composition on Targeting Properties of Radiometal-Labeled Anti-HER2 Scaffold Protein ADAPT6
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. (Vladimir Tolmachev)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. (Vladimir Tolmachev)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. (Vladimir Tolmachev)
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2016 (Engelska)Ingår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 27, nr 11, s. 2678-2688Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2016. Vol. 27, nr 11, s. 2678-2688
Nationell ämneskategori
Radiologi och bildbehandling
Identifikatorer
URN: urn:nbn:se:uu:diva-312075DOI: 10.1021/acs.bioconjchem.6b00465ISI: 000388430700011PubMedID: 27740752OAI: oai:DiVA.org:uu-312075DiVA, id: diva2:1062154
Forskningsfinansiär
Cancerfonden, CAN 2015/350Vetenskapsrådet, 2015-02353Vetenskapsrådet, 621-2012-5088Tillgänglig från: 2017-01-04 Skapad: 2017-01-04 Senast uppdaterad: 2017-11-29Bibliografiskt granskad
Ingår i avhandling
1. Development of ADAPT-based tracers for radionuclide molecular imaging of cancer
Öppna denna publikation i ny flik eller fönster >>Development of ADAPT-based tracers for radionuclide molecular imaging of cancer
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

ABD-Derived Affinity Proteins (ADAPTs) is a novel class of small engineered scaffold proteins based on albumin-binding domain (ABD) of streptococcal protein G. High affinity ADAPT  binders against various therapeutic targets can be selected.  In this thesis, we report a development of ADAPT-based radionuclide imaging agents providing high sensitivity and specificity of molecular imaging of HER2 expression in disseminated cancers.

We investigated the feasibility of the use of ADAPTs as imaging agents and influence of molecular design and radiolabeling chemistry on in vivo targeting and biodistribution properties of the tracers.

In Paper I we demonstrated the feasibility of the use of anti-HER2 ADAPT6 molecule as a high contrast imaging agent;

In Paper II we evaluated the influence of composition of histidine-containing tag on in vivo biodistribution of ADAPT-based tracers labeled with 99mTc using 99mTc(CO)3 binding to histidine-containing tags and 111In using DOTA chelator at N-terminus;

In Paper III we evaluated the influence of different aspects of N-terminus leading sequence on targeting including effect of sequence size on clearance rate and effect of the composition of the sequence on biodistribution profile;

In Paper IV, we evaluated the influence of residualizing properties and positioning of the label on biodistribution and targeting; and

In Paper V, we compared tumor-targeting properties of the ADAPT6 labeled at C-terminus with 99mTc using N3S chelator and 111In using DOTA chelator.

In conclusion, ADAPTs constitute a very promising class of targeting probes for molecular imaging providing high contrast. Molecular design of the ADAPT proteins and chelators/linkers for labeling has an appreciable effect on their imaging properties.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 99
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1354
Nyckelord
ADAPT, scaffold protein, albumin-binding domain (ABD), Affinity protein, HER2, radionuclide molecular imaging
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-327419 (URN)978-91-513-0030-6 (ISBN)
Disputation
2017-09-29, Fåhraeus Hall, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-09-06 Skapad: 2017-08-10 Senast uppdaterad: 2017-09-08

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