Site Selective Antibody-Oligonucleotide Conjugation via Microbial Transglutaminase.

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2019
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Abstract
Nucleic Acid Therapeutics (NATs), including siRNAs and AntiSense Oligonucleotides (ASOs), have great potential to drug the undruggable genome. Targeting siRNAs and ASOs to specific cell types of interest has driven dramatic improvement in efficacy and reduction in toxicity. Indeed, conjugation of tris-GalNAc to siRNAs and ASOs has shown clinical efficacy in targeting diseases driven by liver hepatocytes. However, targeting non-hepatic diseases with oligonucleotide therapeutics has remained problematic for several reasons, including targeting specific cell types and endosomal escape. Monoclonal antibody (mAb) targeting of siRNAs and ASOs has the potential to deliver these drugs to a variety of specific cell and tissue types. However, most conjugation strategies rely on random chemical conjugation through lysine or cysteine residues resulting in conjugate heterogeneity and a distribution of Drug:Antibody Ratios (DAR). To produce homogeneous DAR-2 conjugates with two siRNAs per mAb, we developed a novel two-step conjugation procedure involving microbial transglutaminase (MTGase) tagging of the antibody C-terminus with an azide-functionalized linker peptide that can be subsequently conjugated to dibenzylcyclooctyne (DBCO) bearing oligonucleotides through azide-alkyne cycloaddition. Antibody-siRNA (and ASO) conjugates (ARCs) produced using this strategy are soluble, chemically defined targeted oligonucleotide therapeutics that have the potential to greatly increase the number of targetable cell types.
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huggins2019sitemolecules Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Huggins, Ian J;Medina, Carlos A;Springer, Aaron D;van den Berg, Arjen;Jadhav, Satish;Cui, Xianshu;Dowdy, Steven F;
Journal molecules
Year 2019
DOI
E3287
URL
Keywords
monoclonal antibodies antibody-sirna conjugate (arc) antisense oligonucleotides copper-less click microbial transglutaminase oligonucleotide therapeutics sirna sustainability Fog computing iot smart cities lorawan 3d ray-launching lpwan wireless sensor networks (wsn) outdoor applications smart campus

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