Evaluation of a HER2-targeting affibody molecule combining an N-terminal HEHEHE-tag with a GGGC chelator for 99mTc-labelling at the C terminus
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- 作者：Hanna Lindberg (1)
Camilla Hofstr?m (1)
Mohamed Altai (2)
Hadis Honorvar (2)
Helena W?llberg (1)
Anna Orlova (3)
Stefan St?hl (1)
Torbj?rn Gr?slund (1)
Vladimir Tolmachev (2) - 关键词：Affibody molecules ; Radionuclide molecular imaging ; Technetium ; 99m ; HEHEHE ; tag ; GGGC chelator ; Biodistribution
- 刊名：Tumor Biology
- 出版年：2012
- 出版时间：June 2012
- 年：2012
- 卷：33
- 期：3
- 页码：641-651
- 全文大小：514KB
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31. Tran TA, Rosik D, Abrahmsén L, Sandstr?m M, Sj?berg A, W?llberg H, et al. Design, synthesis and biological evaluation of a multifunctional HER2-specific affibody molecule for molecular imaging. Eur J Nucl Med Mol Imaging. 2009;36:1864-3. CrossRef - 作者单位：Hanna Lindberg (1)
Camilla Hofstr?m (1)
Mohamed Altai (2)
Hadis Honorvar (2)
Helena W?llberg (1)
Anna Orlova (3)
Stefan St?hl (1)
Torbj?rn Gr?slund (1)
Vladimir Tolmachev (2)
1. Division of Molecular Biotechnology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology, Stockholm, Sweden
2. Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, 751 85, Uppsala, Sweden
3. Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Uppsala, Sweden - ISSN：1423-0380
文摘
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 99mTc. 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 His6-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-ZHER2:342-GGGC affibody molecule was generated. It could be efficiently purified by IMAC and stably labelled with 99mTc. 99mTc-(HE)3-ZHER2:342-GGGC preserved specific binding to HER2-expressing cells. In NMRI mice, hepatic uptake of 99mTc-(HE)3-ZHER2:342-GGGC was lower than the uptake of the control affibody molecules, 99mTc-ZHER2:2395-VDC and 99mTc-ZHER2:342-GGGC. At 1 and 4?h after injection, the renal uptake of 99mTc-(HE)3-ZHER2:342-GGGC was 2--fold lower than uptake of 99mTc-ZHER2:2395-VDC, but it was substantially higher than uptake of 99mTc-ZHER2:342-GGGC. Further investigation indicated that a fraction of 99mTc 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 99mTc labelling due to a partial loss of site-specificity of nuclide chelation.