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PET imaging of epidermal growth factor receptor expression in tumours using Zr-89-labelled ZEGFR:2377 affibody molecules
KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
Vise andre og tillknytning
2016 (engelsk)Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 48, nr 4, s. 1325-1332Artikkel i tidsskrift (Fagfellevurdert) Published
Resurstyp
Text
Abstract [en]

Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which is overexpressed in many types of cancer. The use of EGFR-targeting monoclonal antibodies and tyrosine-kinase inhibitors improves significantly survival of patients with colorectal, non-small cell lung cancer and head and neck squamous cell carcinoma. Detection of EGFR overexpression provides important prognostic and predictive information influencing management of the patients. The use of radionuclide molecular imaging would enable non-invasive repeatable determination of EGFR expression in disseminated cancer. Moreover, positron emission tomography (PET) would provide superior sensitivity and quantitation accuracy in EGFR expression imaging. Affibody molecules are a new type of imaging probes, providing high contrast in molecular imaging. In the present study, an EGFR-binding affibody molecule (ZEGFR:2377) was site-specifically conjugated with a deferoxamine (DFO) chelator and labelled under mild conditions (room temperature and neutral pH) with a radionuclide Zr-89. The Zr-89-DFO-ZEGFR:2377 tracer demonstrated specific high affinity (160 +/- 60 pM) binding to EGFR-expressing A431 epidermoid carcinoma cell line. In mice bearing A431 xenografts, Zr-89-DFO-ZEGFR: 2377 demonstrated specific uptake in tumours and EGFR-expressing tissues. The tracer provided tumour uptake of 2.6 +/- 0.5% ID/g and tumour-to-blood ratio of 3.7 +/- 0.6 at 24 h after injection. Zr-89-DFO-ZEGFR: 2377 provides higher tumour-to-organ ratios than anti-EGFR antibody Zr-89-DFO-cetuximab at 48 h after injection. EGFR-expressing tumours were clearly visualized by microPET using Zr-89-DFO-ZEGFR: 2377 at both 3 and 24 h after injection. In conclusion, Zr-89-DFO-ZEGFR: 2377 is a potential probe for PET imaging of EGFR-expression in vivo.

sted, utgiver, år, opplag, sider
Spandidos , 2016. Vol. 48, nr 4, s. 1325-1332
Emneord [en]
epidermal growth factor receptor, affibody molecules, radionuclide imaging, positron emission tomography, zirconium-89, xenografts
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-185347DOI: 10.3892/ijo.2016.3369ISI: 000372567100002Scopus ID: 2-s2.0-84959020465OAI: oai:DiVA.org:kth-185347DiVA, id: diva2:921800
Forskningsfinansiär
Swedish Research CouncilSwedish Cancer Society
Merknad

QC 20160421

Tilgjengelig fra: 2016-04-21 Laget: 2016-04-18 Sist oppdatert: 2017-11-30bibliografisk kontrollert
Inngår i avhandling
1. Combinatorial Protein Engineering Of Affibody Molecules Using E. Coli Display And Rational Design Of Affibody-Based Tracers For Medical Imaging
Åpne denne publikasjonen i ny fane eller vindu >>Combinatorial Protein Engineering Of Affibody Molecules Using E. Coli Display And Rational Design Of Affibody-Based Tracers For Medical Imaging
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Directed evolution is today an established strategy for generation of new affinity proteins. This thesis describes the development of a cell-display method using Escherichia coli for directed evolution of Affibody molecules. Further, the thesis describes rational design of Affibody-based tracers, intended for future patient stratification using medical imaging. Fusing recombinant proteins to various autotransporters is a promising approach for efficient surface display on the surface of E. coli, as well as for construction of high-complexity libraries. In paper I, we successfully engineered an expression vector for display of Affibody molecules using the autotransporter AIDA-I. In paper II, a large Affibody library of 2.3x109 variants was constructed and screening using FACS resulted in new specific binders in the nanomolar range. In paper III, we demonstrated Sortase-mediated secretion and conjugation of binders directly from the E. coli surface. 

The three following studies describe rational design of Affibody-based tracers against two cancer-associated targets for molecular imaging. First, anti-HER3 Affibody molecules were labelled with 111In, and SPECT imaging showed that the conjugates specifically targeted HER3-expressing xenografts. Furthermore, labeling with 68Ga for PET imaging showed that tumor uptake correlated with HER3 expression, suggesting that the tracers have potential for patient stratification. The last study describes the development and investigation of anti-EGFR Affibody-based imaging agents. Labeled with 89Zr, the Affibody tracer demonstrated higher tumor uptake at 3 h post injection than the anti-EGFR antibody cetuximab at 48 h post injection. 

In conclusion, this thesis describes new tools and knowledge that will hopefully contribute to the development of affinity proteins for biotechnology, therapy and medical imaging in the future. 

 

sted, utgiver, år, opplag, sider
Stockholm: KTH Royal Institute of Technology, 2017. s. 80
Serie
TRITA-BIO-Report, ISSN 1654-2312 ; 2017:17
Emneord
directed evolution, microbial display, E. coli, Affibody molecule, autotransporter, medical imaging, HER receptor family, Sortase A
HSV kategori
Forskningsprogram
Bioteknologi
Identifikatorer
urn:nbn:se:kth:diva-213451 (URN)978-91-7729-504-4 (ISBN)
Disputas
2017-10-06, F3, Lindstedtsvägen 26, Sing-Sing, floor 2, KTH Campus, Stockholm, 13:00 (engelsk)
Opponent
Veileder
Merknad

QC 20170904

Tilgjengelig fra: 2017-09-05 Laget: 2017-08-31 Sist oppdatert: 2017-09-05bibliografisk kontrollert

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