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Optimized molecular design of ADAPT-based HER2-imaging probes labelled with 111In and 68Ga
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
Uppsala university.
Uppsala university.
Uppsala university.
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 7, p. 2674-2683Article in journal (Refereed) Published
Abstract [en]

Radionuclide molecular imaging is a promising tool for visualization of cancer associated molecular abnormalities in vivo and stratification of patients for specific therapies. ADAPT is a new type of small engineered proteins based on the scaffold of an albumin binding domain of protein G. ADAPTs have been utilized to select and develop high affinity binders to different proteinaceous targets. ADAPT6 binds to human epidermal growth factor 2 (HER2) with low nanomolar affinity and can be used for its in vivo visualization. Molecular design of 111In-labeled anti-HER2 ADAPT has been optimized in several earlier studies. In this study, we made a direct comparison of two of the most promising variants, having either a DEAVDANS or a (HE)3DANS sequence at the N-terminus, conjugated with a maleimido derivative of DOTA to a GSSC amino acids sequence at the C-terminus. The variants (designated DOTA-C59-DEAVDANS-ADAPT6-GSSC and DOTA-C61-(HE)3DANS-ADAPT6-GSSC) were stably labeled with 111In for SPECT and 68Ga for PET. Biodistribution of labeled ADAPT variants was evaluated in nude mice bearing human tumor xenografts with different levels of HER2 expression. Both variants enabled clear discrimination between tumors with high and low levels of HER2 expression. 111In-labeled ADAPT6 derivatives provided higher tumor-to-organ ratios compared to 68Ga-labeled counterparts. The best performing variant was DOTA-C61-(HE)3DANS-ADAPT6-GSSC, which provided tumor-to-blood ratios of 208 ± 36 and 109 ± 17 at 3 h for 111In and 68Ga labels, respectively.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018. Vol. 15, no 7, p. 2674-2683
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-238508DOI: 10.1021/acs.molpharmaceut.8b00204ISI: 000448490100018PubMedID: 29865791Scopus ID: 2-s2.0-85048138088OAI: oai:DiVA.org:kth-238508DiVA, id: diva2:1260594
Funder
Swedish Cancer Society, CAN 2015/350 2017/425Swedish Research Council, 2015-02353 2015-02509VINNOVA, 2016-04060
Note

QC 20181213

Available from: 2018-11-04 Created: 2018-11-04 Last updated: 2020-03-09Bibliographically approved

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Lindbo, SarahHober, Sophia

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Protein TechnologySchool of Engineering Sciences in Chemistry, Biotechnology and Health (CBH)Centre for Bioprocess Technology, CBioPTScience for Life Laboratory, SciLifeLabAlbanova VinnExcellence Center for Protein Technology, ProNova
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Molecular Pharmaceutics
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

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