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186Re-maSGS-ZHER2:342, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours

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Abstract

Purpose

Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule ZHER2:342 has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for 99mTc-labelling, we have found that synthetic ZHER2:342 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.

Methods

maGGG-ZHER2:342 and maGSG-ZHER2:342 were labelled with 186Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by 186Re-maGSG-ZHER2:342 were studied.

Results

Gluconate-mediated labelling of maGGG-ZHER2:342 and maGSG-ZHER2:342 with 186Re 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 186Re-maGGG-ZHER2:342 and 186Re-maGSG-ZHER2:342 demonstrated lower renal uptake than their 99mTc-labelled counterparts. 186Re-maGSG-ZHER2:342 provided the lowest uptake in healthy tissues. Biodistribution of 186Re-maGSG-ZHER2:342 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.

Conclusion

Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.

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Acknowledgments

This study was supported by grants from the Swedish Cancer Society (Cancerfonden) and the Swedish Research Council (Vetenskapsrådet).

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Authors and Affiliations

  1. Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, 751 81, Uppsala, Sweden

    Anna Orlova, Thuy A. Tran & Vladimir Tolmachev

  2. School of Biotechnology, Division of Molecular Biotechnology, Royal Institute of Technology, Stockholm, Sweden

    Torun Ekblad & Amelie Eriksson Karlström

  3. Division of Nuclear Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    Vladimir Tolmachev

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  1. Anna Orlova
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  2. Thuy A. Tran
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  5. Vladimir Tolmachev
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Correspondence to Anna Orlova.

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Orlova, A., Tran, T.A., Ekblad, T. et al. 186Re-maSGS-ZHER2:342, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours. Eur J Nucl Med Mol Imaging 37, 260–269 (2010). https://doi.org/10.1007/s00259-009-1268-9

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  • DOI: https://doi.org/10.1007/s00259-009-1268-9

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