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Evaluation of radiocobalt-labelled affibody molecule for imaging of human epidermal growth factor receptor 3 expression
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
Vise andre og tillknytning
2017 (engelsk)Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 51, nr 6, s. 1765-1774Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2017. Vol. 51, nr 6, s. 1765-1774
Emneord [en]
HER3, affibody, PET imaging, Cobalt-55/57, NOTA-chelator
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-343404DOI: 10.3892/ijo.2017.4152ISI: 000416685600014OAI: oai:DiVA.org:uu-343404DiVA, id: diva2:1185995
Forskningsfinansiär
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, 2016-04060Tilgjengelig fra: 2018-02-27 Laget: 2018-02-27 Sist oppdatert: 2018-09-20bibliografisk kontrollert
Inngår i avhandling
1. Affibody Molecules for HER3-targeted Theranostics of Malignant Tumours
Åpne denne publikasjonen i ny fane eller vindu >>Affibody Molecules for HER3-targeted Theranostics of Malignant Tumours
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 62
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 258
Emneord
affibody molecules, theranostics, HER3, molecular imaging
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-360973 (URN)978-91-513-0449-6 (ISBN)
Disputas
2018-11-09, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-10-17 Laget: 2018-09-20 Sist oppdatert: 2018-11-19

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