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European Journal of Nuclear Medicine and Molecular Imaging

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01-11-2007 | Original Article

^99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule

Authors: Torun Engfeldt, Thuy Tran, Anna Orlova, Charles Widström, Joachim Feldwisch, Lars Abrahmsen, Anders Wennborg, Amelie Eriksson Karlström, Vladimir Tolmachev

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 11/2007

Abstract

Purpose

Monitoring HER2 expression is crucial for selection of breast cancer patients amenable to HER2-targeting therapy. The Affibody molecule Z_HER2:342 binds to HER2 with picomolar affinity and enables specific imaging of HER2 expression. Previously, Z_HER2:342 with the additional N-terminal mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) sequence was labelled with ^99mTc and demonstrated specific targeting of HER2-expressing xenografts. However, hepatobiliary excretion caused high radioactivity accumulation in the abdomen. We investigated whether the biodistribution of Z_HER2:342 can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues.

Methods

The Affibody molecule Z_HER2:342, carrying the chelators mercaptoacetyl-glycyl-seryl-glycyl (maGSG), mercaptoacetyl-glycyl-D-seryl-glycyl [maG(D-S)G] and mercaptoacetyl-seryl-seryl-seryl (maSSS), were prepared by peptide synthesis and labelled with ^99mTc. The differences in the excretion pathways were evaluated in normal mice. The tumour targeting capacity of ^99mTc-maSSS-Z_HER2:342 was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated Z_HER2:342.

Results

A shift towards renal excretion was obtained when glycine was substituted with serine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced threefold for the maSSS conjugate in comparison with the maGGG conjugate 4 h post injection (p.i.). The tumour uptake of ^99mTc-maSSS-Z_HER2:342 was 11.5 ± 0.5% IA/g 4 h p.i., and the tumour-to-blood ratio was 76. The pharmacokinetics and uptake characteristics of technetium-labelled Z_HER2:342 were better than those of radioiodinated Z_HER2:342.

Conclusion

The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule Z_HER2:342 compared with glycyl-containing chelators and is favourable for imaging of tumours and metastases in the abdominal area.

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Title: 99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule
Authors: Torun Engfeldt
Thuy Tran
Anna Orlova
Charles Widström
Joachim Feldwisch
Lars Abrahmsen
Anders Wennborg
Amelie Eriksson Karlström
Vladimir Tolmachev
Publication date: 01-11-2007
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 11/2007
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-007-0474-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

^99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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