targeted sirna delivery and mrna knockdown mediated by bispecific digoxigenin-binding antibodies

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ID: 148307
2012
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Abstract
Bispecific antibodies (bsAbs) that bind to cell surface antigens and to digoxigenin (Dig) were used for targeted small interfering RNA (siRNA) delivery. They are derivatives of immunoglobulins G (IgGs) that bind tumor antigens, such as Her2, IGF1-R, CD22, and LeY, with stabilized Dig-binding variable domains fused to the C-terminal ends of the heavy chains. siRNA that was digoxigeninylated at its 3′end was bound in a 2:1 ratio to the bsAbs. These bsAb–siRNA complexes delivered siRNAs specifically to cells that express the corresponding antigen as demonstrated by flow cytometry and confocal microscopy. The complexes internalized into endosomes and Dig-siRNAs separated from bsAbs, but Dig-siRNA was not released into the cytoplasm; bsAb-targeting alone was thus not sufficient for effective mRNA knockdown. This limitation was overcome by formulating the Dig-siRNA into nanoparticles consisting of dynamic polyconjugates (DPCs) or into lipid-based nanoparticles (LNPs). The resulting complexes enabled bsAb-targeted siRNA-specific messenger RNA (mRNA) knockdown with IC50 siRNA values in the low nanomolar range for a variety of bsAbs, siRNAs, and target cells. Furthermore, pilot studies in mice bearing tumor xenografts indicated mRNA knockdown in endothelial cells following systemic co-administration of bsAbs and siRNA formulated in LNPs that were targeted to the tumor vasculature.
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schneider2012moleculartargeted Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Britta Schneider;Michael Grote;Matthias John;Alexander Haas;Birgit Bramlage;Ludger M lckenstein;Kerstin Jahn-Hofmann;Frieder Bauss;Weijun Cheng;Rebecca Croasdale;Karin Daub;Simone Dill;Eike Hoffmann;Wilma Lau;Helmut Burtscher;James L Ludtke;Silke Metz;Olaf Mundigl;Zane C Neal;Werner Scheuer;Jan Stracke;Hans Herweijer;Ulrjch Brinkmann
Journal coordination chemistry reviews
Year 2012
DOI
10.1038/mtna.2012.39
URL
http://www.sciencedirect.com/science/article/pii/S2162253116301032
Keywords
rna interference bispecific antibody pharmacology

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