Document Detail

Development of (177) Lu-nanobodies for radioimmunotherapy of HER2-positive breast cancer: evaluation of different bifunctional chelators.
MedLine Citation:
PMID:  22434639     Owner:  NLM     Status:  In-Data-Review    
Nanobodies show favourable pharmacokinetic characteristics for tumor targeting, including high tumor-to-background-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. The choice of the bifunctional chelator could affect the in vivo behaviour of the radiolabeled nanobody. Consequently, 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-to-background ratios. No specific binding was observed in a HER2-negative model. In conclusion, the in-house developed anti-HER2 nanobody 2Rs15dHIS can be successfully labeled with (177) Lu using different bifunctional chelators. Both macrocyclic and acyclic chelators show high stability in time. High specific tumor uptake combined with the lowest background uptake was measured using the 1B4M-DTPA-based conjugate. Copyright © 2012 John Wiley & Sons, Ltd.
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
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Contrast media & molecular imaging     Volume:  7     ISSN:  1555-4317     ISO Abbreviation:  Contrast Media Mol Imaging     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101286760     Medline TA:  Contrast Media Mol Imaging     Country:  United States    
Other Details:
Languages:  eng     Pagination:  254-64     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 John Wiley & Sons, Ltd.
Radiobiology Unit, Molecular and Cellular Biology Expert Group, Belgian Nuclear Research Center (SCK•CEN), Mol, Belgium; In vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
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