Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Evaluation of radiocobalt-labelled affibody molecule for imaging of human epidermal growth factor receptor 3 expression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
Show others and affiliations
2017 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 51, no 6, p. 1765-1774Article in journal (Refereed) Published
Abstract [en]

The human epidermal growth factor receptor 3 (HER3) is involved in the development of cancer resistance towards tyrosine kinase-targeted therapies. Several HER3‑targeting therapeutics are currently under clinical evaluation. Non-invasive imaging of HER3 expression could improve patient management. Affibody molecules are small engineered scaffold proteins demonstrating superior properties as targeting probes for molecular imaging compared with monoclonal antibodies. Feasibility of in vivo HER3 imaging using affibody molecules has been previously demonstrated. Preclinical studies have shown that the contrast when imaging using anti-HER3 affibody molecules can be improved over time. We aim to develop an agent for PET imaging of HER3 expression using the long-lived positron-emitting radionuclide cobalt-55 (55Co) (T1/2=17.5 h). A long-lived cobalt isotope 57Co was used as a surrogate for 55Co in this study. The anti-HER3 affibody molecule HEHEHE-ZHER3-NOTA was labelled with radiocobalt with high yield, purity and stability. Biodistribution of 57Co-HEHEHE-ZHER3-NOTA was measured in mice bearing DU145 (prostate carcinoma) and LS174T (colorectal carcinoma) xenografts at 3 and 24 h post injection (p.i.). Tumour-to-blood ratios significantly increased between 3 and 24 h p.i. (p<0.05). At 24 h p.i., tumour-to-blood ratios were 6 for DU145 and 8 for LS174T xenografts, respectively. HER3‑expressing xenografts were clearly visualized in a preclinical imaging setting already 3 h p.i., and contrast further improved at 24 h p.i. In conclusion, the radiocobalt-labelled anti-HER3 affibody molecule, HEHEHE-ZHER3-NOTA, is a promising tracer for imaging of HER3 expression in tumours.

Place, publisher, year, edition, pages
2017. Vol. 51, no 6, p. 1765-1774
Keywords [en]
HER3, affibody, PET imaging, Cobalt-55/57, NOTA-chelator
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-343404DOI: 10.3892/ijo.2017.4152ISI: 000416685600014OAI: oai:DiVA.org:uu-343404DiVA, id: diva2:1185995
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer Society, CAN2014/474Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Research Council, 2012-05236Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN2016/463VINNOVA, 2016-04060Available from: 2018-02-27 Created: 2018-02-27 Last updated: 2018-09-20Bibliographically approved
In thesis
1. Affibody Molecules for HER3-targeted Theranostics of Malignant Tumours
Open this publication in new window or tab >>Affibody Molecules for HER3-targeted Theranostics of Malignant Tumours
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The HER3 receptor plays a strong role in disease progression and resistance to therapies in several cancer types. Due to its endogenous expression and low overexpression in malignant tumours, it is a particularly challenging target. The primary aim of this thesis project was to develop, evaluate and characterize affibody molecules for theranostic applications in HER3-expressing malignant tumours.

Paper I investigated the in vivo targeting properties and therapeutic efficacy of a bivalent affibody construct fused with an albumin binding domain, ZHER3-ABD-ZHER3. This construct could slow down the growth of HER3-expressing tumour xenografts without causing health problems or side effects in mice.

Paper II compared the in vitro and in vivo properties of two HER3-targeting affibody molecules (Z08698 and Z08699) to select an imaging probe for HER3 diagnostics. While the two constructs had similar properties, Z08698 demonstrated better blood clearance and better radioactivity retention in tumours.

Paper III and IV present the development of a HER3 imaging probe for PET using gallium and cobalt isotopes. We demonstrated that imaging of HER3 expression could be obtained as soon as 3 h pi using gallium-68. Additionally, we demonstrated that affibody molecules labelled with a neutral cobalt-NOTA complex had a lower radioactivity uptake in the liver than molecules radiolabelled with a positive gallium-NOTA complex. Imaging contrast increased over time. As the dose of the injected protein increased, the activity uptake in normal organs decreased, whereas the tumour uptake remained the same, which improved the imaging contrast and allowed discrimination between xenografts with high and low HER3 expression. This modification did not influence tumour activity uptake.

Paper V presents the HER3-targeting affibody molecule trimer as a tool to block hepatic uptake in order to increase the imaging contrast in the liver. The trimer demonstrated its ability to bind to endogenous receptors in the liver, which decreased the hepatic uptake of the radiolabelled monomer. This phenomenon enabled the monomer to pass the liver barrier, which increased tumour radioactivity uptake and improved imaging contrast.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 258
Keywords
affibody molecules, theranostics, HER3, molecular imaging
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-360973 (URN)978-91-513-0449-6 (ISBN)
Public defence
2018-11-09, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-10-17 Created: 2018-09-20 Last updated: 2018-11-19

Open Access in DiVA

fulltext(653 kB)11 downloads
File information
File name FULLTEXT01.pdfFile size 653 kBChecksum SHA-512
ea15b788fa6c68bbbb6e1a800f8133e74c2099032a2ccb6304da0818935b9c4d118902be1e101ff97040b2bd058cb239a7ffc1297d00d0511c31a507aaf82401
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Rosestedt, MariaMitran, BogdanRinne, Sara S.Tolmachev, VladimirOrlova, Anna
By organisation
TheranosticsMedical Radiation Science
In the same journal
International Journal of Oncology
Radiology, Nuclear Medicine and Medical Imaging

Search outside of DiVA

GoogleGoogle Scholar
Total: 11 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 42 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf