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

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

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)


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, ZHER2:342 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 ZHER2:342 can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues. Methods: The Affibody molecule ZHER2:342, 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-ZHER2:342 was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated ZHER2:342. 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-ZHER2:342 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 ZHER2:342 were better than those of radioiodinated ZHER2:342. Conclusion: The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule ZHER2:342 compared with glycyl-containing chelators and is favourable for imaging of tumours and metastases in the abdominal area.

Original languageEnglish
Pages (from-to)1843-1853
Number of pages11
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Issue number11
Publication statusPublished - Nov 2007
Externally publishedYes


  • Affibody molecule
  • HER2
  • Peptide synthesis
  • Technetium-99m
  • Tumour targeting

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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