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European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

01.09.2009 | Original Article

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

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

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 9/2009

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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-(Z_HER2:342)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-(Z_HER2:342)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-(Z_HER2:342)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.

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Titel: 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
verfasst von: Vladimir Tolmachev
Helena Wållberg
Karl Andersson
Anders Wennborg
Hans Lundqvist
Anna Orlova
Publikationsdatum: 01.09.2009
Verlag: Springer-Verlag
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 9/2009
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-009-1134-9

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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

Abstract

Purpose

Methods

Results

Conclusion

Live-Webinar "Chronische Unterbauch- und Viszeralschmerzen in der Praxis managen"

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

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