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Evaluation of a HER2-targeting affibody molecule combining an N-terminal HEHEHE-tag with a GGGC chelator for Tc-99m-labelling at the C terminus
KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi (stängd 20130101).ORCID-id: 0000-0002-5192-7362
KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi (stängd 20130101).
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2012 (engelsk)Inngår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, nr 3, s. 641-651Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Affibody molecules are a class of small (ca.7 kDa) robust scaffold proteins with high potential as tracers for radionuclide molecular imaging in vivo. Incorporation of a cysteine-containing peptide-based chelator at the C terminus provides an opportunity for stable labelling with the radionuclide Tc-99m. The use of a GGGC chelator at the C terminus has provided the lowest renal radioactivity retention of the previously investigated peptide-based chelators. Previously, it has also been demonstrated that replacement of the His(6)-tag with the negatively charged histidine-glutamate-histidine-glutamate-histidine-glutamate (HEHEHE)-tag permits purification of affibody molecules by immobilized metal ion affinity chromatography (IMAC) and provides low hepatic accumulation of radioactivity of conjugates site-specifically labelled at the C terminus using several different nuclides. We hypothesized that the combination of a HEHEHE-tag at the N terminus and a GGGC chelator at the C terminus of an affibody molecule would be a favourable format permitting IMAC purification and providing low uptake in excretory organs. To investigate this hypothesis, a (HE)(3)-Z(HER2:342)-GGGC affibody molecule was generated. It could be efficiently purified by IMAC and stably labelled with Tc-99m. Tc-99m-(HE)(3)-Z(HER2:342)-GGGC preserved specific binding to HER2-expressing cells. In NMRI mice, hepatic uptake of Tc-99m-(HE)(3)-Z(HER2:342)-GGGC was lower than the uptake of the control affibody molecules, Tc-99m-Z(HER2:2395)-VDC and Tc-99m-Z(HER2:342)-GGGC. At 1 and 4 h after injection, the renal uptake of Tc-99m-(HE)(3)-Z(HER2:342)-GGGC was 2-3-fold lower than uptake of Tc-99m-Z(HER2:2395)-VDC, but it was substantially higher than uptake of Tc-99m-Z(HER2:342)-GGGC. Further investigation indicated that a fraction of Tc-99m was chelated by the HEHEHE-tag which caused a higher accumulation of radioactivity in the kidneys. Thus, a combination of a HEHEHE-tag and the GGGC chelator in targeting scaffold proteins was found to be undesirable in the case of Tc-99m labelling due to a partial loss of site-specificity of nuclide chelation.

sted, utgiver, år, opplag, sider
Springer, 2012. Vol. 33, nr 3, s. 641-651
Emneord [en]
Affibody molecules, Radionuclide molecular imaging, Technetium-99m, HEHEHE-tag, GGGC chelator, Biodistribution
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-96436DOI: 10.1007/s13277-011-0305-zISI: 000303530200008Scopus ID: 2-s2.0-84863581172OAI: oai:DiVA.org:kth-96436DiVA, id: diva2:531395
Forskningsfinansiär
Swedish Research Council
Merknad

QC 20120607

Tilgjengelig fra: 2012-06-07 Laget: 2012-06-04 Sist oppdatert: 2017-12-07bibliografisk kontrollert

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Lindberg, HannaStåhl, StefanGräslund, Torbjörn

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