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

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Tolmachev, VladimirUppsala universitet,Institutionen för medicinska vetenskaper (author)

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

Article/chapterEnglish2009

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2009-05-09
Springer Science and Business Media LLC,2009
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LIBRIS-ID:oai:DiVA.org:uu-128315
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-128315URI
https://doi.org/10.1007/s00259-009-1134-9DOI

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Language:English
Summary in:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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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.

Subject headings and genre

Affibody molecule
In-114m
Biodistribution
Radionuclide therapy
Albumin-binding domain
MEDICINE
MEDICIN

Added entries (persons, corporate bodies, meetings, titles ...)

Wallberg, Helena (author)
Andersson, KarlUppsala universitet,Enheten för biomedicinsk strålningsvetenskap (author)
Wennborg, Anders (author)
Lundqvist, HansUppsala universitet,Enheten för biomedicinsk strålningsvetenskap(Swepub:uu)hanslund (author)
Orlova, AnnaUppsala universitet,Enheten för biomedicinsk strålningsvetenskap(Swepub:uu)annaorlo (author)
Uppsala universitetInstitutionen för medicinska vetenskaper (creator_code:org_t)

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In:European Journal of Nuclear Medicine and Molecular Imaging: Springer Science and Business Media LLC36:9, s. 1460-14681619-70701619-7089

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