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Open AccessArticle

Site Selective Antibody-Oligonucleotide Conjugation via Microbial Transglutaminase

1
Department of Cellular and Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
2
Sorrento Therapeutics, San Diego, CA 92121, USA
3
Life Technologies, Thermo Fisher Scientific, Frederick, MD 21703, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Roger Strömberg
Molecules 2019, 24(18), 3287; https://doi.org/10.3390/molecules24183287
Received: 2 August 2019 / Revised: 6 September 2019 / Accepted: 9 September 2019 / Published: 10 September 2019
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. View Full-Text
Keywords: oligonucleotide therapeutics; siRNA; antisense oligonucleotides; monoclonal antibodies; antibody-siRNA conjugate (ARC); microbial transglutaminase; copper-less click oligonucleotide therapeutics; siRNA; antisense oligonucleotides; monoclonal antibodies; antibody-siRNA conjugate (ARC); microbial transglutaminase; copper-less click
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Huggins, I.J.; Medina, C.A.; Springer, A.D.; van den Berg, A.; Jadhav, S.; Cui, X.; Dowdy, S.F. Site Selective Antibody-Oligonucleotide Conjugation via Microbial Transglutaminase. Molecules 2019, 24, 3287.

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