The influence of Bz-DOTA and CHX-A″-DTPA on the biodistribution of ABD-fused anti-HER2 Affibody molecules: Implications for 114mIn- mediated targeting therapy

Vladimir Tolmachev, Helena Wållberg, Karl Andersson, Anders Wennborg, Hans Lundqvist, Anna Orlova

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Purpose: Affibody molecules represent a novel class of high-affinity agents for radionuclide tumour targeting. Fusion of the Affibody molecules with an albumin-binding domain (ABD) enables modification of the blood kinetics of the Affibody molecules and reduction of the renal dose. 177Lu-CHX- A″-DTPA-ABD-(ZHER2:342)2, an anti-HER2 Affibody molecule-ABD fusion protein has earlier demonstrated promising results in treatment of HER2-expressing micro-xenografts in mice. The use of the in vivo generator 114mIn/114In as a label for ABD-fused Affibody molecules would create preconditions for efficient treatment of both micrometastases (due to conversion and Auger electrons of 114mIn) and bulky tumours (due to high-energy beta particles from the daughter nuclide 114In). The goal of this study was to investigate if different chelators influence the biodistribution of ABD-(ZHER2:342) 2 and to find an optimal chelator for attachment of 114mIn to the Affibody molecule-ABD fusion protein. Methods: Isothiocyanate derivatives of Bz-DOTA and CHX-A″-DTPA were coupled to ABD-(Z HER2:342)2. The cellular processing of both conjugates was studied in vitro. The influence of chelators on the biodistribution was investigated in mice using double isotope (114mIn and 111In) labelling. Results: The apparent affinity of CHX-A″-DTPA-ABD-(ZHER2:342)2 and Bz-DOTA-ABD-(Z HER2:342)2 to the extracellular domain of HER2 was similar, 13.5 and 15.0 pM, respectively. It was found that both conjugates were internalized by SKOV-3 cells. The use of CHX-A″-DTPA provided better cellular retention of the radioactivity, better tumour accumulation of radioactivity and better tumour to organ dose ratios than Bz-DOTA-ABD-(Z HER2:342)2. Conclusion: CHX-A″-DTPA is more suitable for 114mIn labelling of Affibody molecule-ABD fusion proteins for radionuclide therapy.

Original languageEnglish
Pages (from-to)1460-1468
Number of pages9
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume36
Issue number9
DOIs
Publication statusPublished - Sep 2009
Externally publishedYes

Keywords

  • In
  • Affibody molecule
  • Albumin-binding domain
  • Biodistribution
  • Radionuclide therapy

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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