Development of 177Lu-nanobodies for radioimmunotherapy of HER2-positive breast cancer: evaluation of different bifunctional chelators

Matthias D'huyvetter, An Aerts, Catarina Xavier, Ilse Vaneycken, Nick Devoogdt, Marlies Gijs, Nathalie Impens, Sarah Baatout, Bernard Ponsard, Serge Muyldermans, Vicky Caveliers, Tony Lahoutte

    Research outputpeer-review


    Nanobodies show favourable pharmacokinetic characteristics for tumor targeting, including high tumor-tobackground-ratios. Labelled with a therapeutic radionuclide, nanobodies could be used as an adjuvant treatment option for HER2-overexpressing minimal residual disease. The therapeutic radionuclide Lutetium-177 is linked to the nanobody using a bifunctional chelator. We compared four different bifunctional chelators - p-SCN-Bn-DOTA, DOTA-NHS-ester, CHX-A”-DTPA or 1B4M-DTPA - in order to select the optimal chemical link between Lutetium-177 and a HER2 targeting nanobody. MS results revealed different degrees of chelator-conjugation. High stability in time was observed, together with nanomolar affinities on HER2-expressing tumor cells. Ex vivo biodistributions as well as SPECT/micro-CT analyses showed high activities in tumors expressing medium HER2 levels with low background activity except for the kidneys. The 1B4M-DTPA-coupled conjugate was further evaluated in a high HER2-expressing tumor model. Here, tumor uptake values of 5.99_0.63, 5.12_0.17, 2.83_0.36 and 2.47_0.38 %IA/g were obtained at 1, 3, 24 and 48h p.i., which coincided with exceptionally low background values, except for the kidneys, and unprecedented tumor-tobackground ratios. No specific binding was observed in a HER2-negative model. High specific tumor uptake combined with the lowest background uptake was measured using the 1B4M-DTPA-based conjugate.
    Original languageEnglish
    Pages (from-to)254-264
    JournalContrast Media & Molecular Imaging
    Issue number2
    StatePublished - Apr 2012

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