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Re-186-maSGS-Z(HER2:342), a potential Affibody conjugate for systemic therapy of HER2-expressing tumours
KTH, School of Biotechnology (BIO), Molecular Biotechnology.
KTH, School of Biotechnology (BIO), Molecular Biotechnology.ORCID iD: 0000-0002-0695-5188
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2010 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 37, no 2, 260-269 p.Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z(HER2:342) has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for Tc-99m-labelling, we have found that synthetic Z(HER2:342) conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. maGGG-Z(HER2:342) and maGSG-Z(HER2:342) were labelled with Re-186 and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by Re-186-maGSG-Z(HER2:342) were studied. Gluconate-mediated labelling of maGGG-Z(HER2:342) and maGSG-Z(HER2:342) with Re-186 provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both Re-186-maGGG-Z(HER2:342) and Re-186-maGSG-Z(HER2:342) demonstrated lower renal uptake than their Tc-99m-labelled counterparts. Re-186-maGSG-Z(HER2:342) provided the lowest uptake in healthy tissues. Biodistribution of Re-186-maGSG-Z(HER2:342) in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84 +/- 0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.

Place, publisher, year, edition, pages
2010. Vol. 37, no 2, 260-269 p.
Keyword [en]
Rhenium, Affibody molecules, Chelator, Mercaptoacetyl, HER2, renal-cell carcinoma, monoclonal-antibody, malignant-tumors, binding-proteins, her2 expression, nude-mice, in-vitro, molecule, tc-99m, cancer
National Category
Medical Laboratory and Measurements Technologies
URN: urn:nbn:se:kth:diva-19181DOI: 10.1007/s00259-009-1268-9ISI: 000274293900008ScopusID: 2-s2.0-77949268342OAI: diva2:337228
Swedish Research Council
QC 20110124Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2011-01-24Bibliographically approved

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Ekblad, TorunEriksson Karlström, Amelie
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