Development and preclinical characterisation of 99mTc-labelled Affibody molecules with reduced renal uptake

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

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61 Citations (Scopus)

Abstract

Affibody molecules are low molecular weight proteins (7 kDa), which can be selected to bind to tumour-associated target proteins with subnanomolar affinity. Because of rapid tumour localisation and clearance from nonspecific compartments, Affibody molecules are promising tracers for molecular imaging. Earlier, 99mTc-labelled Affibody molecules demonstrated specific targeting of tumour xenografts. However, the biodistribution was suboptimal either because of hepatobiliary excretion or high renal uptake of the radioactivity. The goal of this study was to optimise the biodistribution of Affibody molecules by chelator engineering. Anti-HER2 ZHER2:342 Affibody molecules, carrying the mercaptoacetyl-glutamyl-seryl-glutamyl (maESE), mercaptoacetyl-glutamyl-glutamyl-seryl (maEES) and mercaptoacetyl-seryl- glutamyl-glutamyl (maSEE) chelators, were prepared by peptide synthesis and labelled with 99mTc. The tumour-targeting capacity of these conjugates was compared with each other and with the best previously available conjugate, 99mTc-maEEE-ZHER2:342, in nude mice bearing SKOV-3 xenografts. The tumour-targeting capacity of the most promising conjugate, 99mTc-maESE-ZHER2:342, was compared with radioiodinated ZHER2:342. All novel conjugates demonstrated successful tumour targeting and a low degree of hepatobiliary excretion. The renal uptakes of serine-containing conjugates, 33∈±∈5, 68∈±∈21 and 71∈±∈10%IA/g, for 99mTc-maESE-ZHER2:342, 99mTc-maEES-Z HER2:342 and 99mTc-maSEE-ZHER2:342, respectively, were significantly reduced in comparison with 99mTc- maEEE-ZHER2:342 (102∈±∈13%IA/g). For 99mTc-maESE-ZHER2:342, a tumour uptake of 9.6∈±∈1.8%IA/g and a tumour-to-blood ratio of 58∈±∈6 were reached at 4 h p.i. A combination of serine and glutamic acid residues in the chelator sequence confers increased renal excretion and relatively low renal uptake of 99mTc-labelled Affibody molecules. In combination with preserved targeting capacity, this improved imaging of targets in abdominal area.

Original languageEnglish
Pages (from-to)2245-2255
Number of pages11
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume35
Issue number12
DOIs
Publication statusPublished - Dec 2008
Externally publishedYes

Keywords

  • Affibody molecule
  • HER2
  • Renal uptake
  • Technetium-99m
  • Tumour targeting

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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