The influence of Bz-DOTA and CHX-AaEuro(3)-DTPA on the biodistribution of ABD-fused anti-HER2 Affibody molecules: implications for In-114m-mediated targeting therapy
2009 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 36, no 9, 1460-1468 p.Article in journal (Refereed) Published
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. Lu-177-CHX-AaEuro(3)-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 In-114m/In-114 as a label for ABD-fused Affibody molecules would create preconditions for efficient treatment of both micrometastases (due to conversion and Auger electrons of In-114m) and bulky tumours (due to high-energy beta particles from the daughter nuclide In-114). 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 In-114m to the Affibody molecule-ABD fusion protein. Isothiocyanate derivatives of Bz-DOTA and CHX-AaEuro(3)-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 (In-114m and In-111) labelling. The apparent affinity of CHX-AaEuro(3)-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-AaEuro(3)-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). CHX-AaEuro(3)-DTPA is more suitable for In-114m labelling of Affibody molecule-ABD fusion proteins for radionuclide therapy.
Place, publisher, year, edition, pages
2009. Vol. 36, no 9, 1460-1468 p.
Affibody molecule, In-114m, Biodistribution, Radionuclide therapy, Albumin-binding domain
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-128315DOI: 10.1007/s00259-009-1134-9ISI: 000268872200013OAI: oai:DiVA.org:uu-128315DiVA: diva2:331258