Radionuclide therapy of HER2-positive microxenografts using a 177Lu-labeled HER2-specific affibody molecule

Vladimir Tolmachev, Anna Orlova, Rikard Pehrson, Joakim Galli, Barbro Baastrup, Karl Andersson, Mattias Sandström, Daniel Rosik, Jörgen Carlsson, Hans Lundqvist, Anders Wennborg, Fredrik Y. Nilsson

Результат исследований: Материалы для журналаСтатьярецензирование

171 Цитирования (Scopus)

Аннотация

A radiolabeled anti-HER2 Affibody molecule (ZHER2:342) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (∼7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy. The dimeric Affibody molecule (ZHER2:342)2 was fused with an albumin-binding domain (ABD) conjugated with the isothiocyanate derivative of CHX-A″-DTPA and labeled with the low-energy β-emitter 177Lu. The obtained conjugate [CHX-A″-DTPA-ABD-(Z HER2:342)2] had a dissociation constant of 18 pmol/L to HER2 and 8.2 and 31 nmol/L for human and murine albumin, respectively. The radiolabeled conjugate displayed specific binding to HER2-expressing cells and good cellular retention in vitro. In vivo, fusion with ABD enabled a 25-fold reduction of renal uptake in comparison with the nonfused dimer molecule (Z HER2:342)2. Furthermore, the biodistribution showed high and specific uptake of the conjugate in HER2-expressing tumors. Treatment of SKOV-3 microxenografts (high HER2 expression) with 17 or 22 MBq 177Lu-CHX-A″-DTPA-ABD-(ZHER2:342)2 completely prevented formation of tumors, in contrast to mice given PBS or 22 MBq of a radiolabeled non-HER2-binding Affibody molecule. In LS174T xenografts (low HER2 expression), this treatment resulted in a small but significant increase of the survival time. Thus, fusion with ABD improved the in vivo biodistribution, and the results highlight 177Lu-CHX-A″-DTPA- ABD-(ZHER2:342)2 as a candidate for treatment of disseminated tumors with a high level of HER2 expression.

Язык оригиналаАнглийский
Страницы (с-по)2773-2782
Число страниц10
ЖурналCancer Research
Том67
Номер выпуска6
DOI
СостояниеОпубликовано - 15 мар 2007
Опубликовано для внешнего пользованияДа

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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