TY - JOUR
T1 - The influence of Bz-DOTA and CHX-A″-DTPA on the biodistribution of ABD-fused anti-HER2 Affibody molecules
T2 - Implications for 114mIn- mediated targeting therapy
AU - Tolmachev, Vladimir
AU - Wållberg, Helena
AU - Andersson, Karl
AU - Wennborg, Anders
AU - Lundqvist, Hans
AU - Orlova, Anna
N1 - Funding Information:
Acknowledgement This study was financially supported by a grant from the Swedish Cancer Society. The authors thank Dr. Fredrik Y Frejd (Affibody AB) for stimulating discussions. We thank also Veronika Eriksson and the staff of the animal facility of Rudbeck Laboratory for technical assistance. The authors also wish to thank the personnel of the Svedberg Laboratory, Uppsala, Sweden, especially Lars Einarsson, for technical support in the production of 114mIn.
Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2009/9
Y1 - 2009/9
N2 - 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.
AB - 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.
KW - In
KW - Affibody molecule
KW - Albumin-binding domain
KW - Biodistribution
KW - Radionuclide therapy
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U2 - 10.1007/s00259-009-1134-9
DO - 10.1007/s00259-009-1134-9
M3 - Article
C2 - 19430786
AN - SCOPUS:68949202319
VL - 36
SP - 1460
EP - 1468
JO - European Journal of Nuclear Medicine and Molecular Imaging
JF - European Journal of Nuclear Medicine and Molecular Imaging
SN - 1619-7070
IS - 9
ER -