An albumin-oligonucleotide assembly for potential combinatorial drug delivery and half-life extension applications

Matthias Kuhlmann, Jonas Bohn Refslund Hamming, Anders Voldum, Georgia Tsakiridou, Maja Thim Larsen, Julie Schmøkel, Emil Sohn, Konrad Bienk, David Henning Schaffert, Esben Skipper Sørensen, Jesper Wengel, Daniel Miotto Dupont, Ken Howard

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

The long blood circulatory property of human serum albumin, due to engagement with the cellular recycling neonatal Fc receptor (FcRn), is an attractive drug half-life extension enabling technology. This work describes a novel site-specific albumin double-stranded (ds) DNA assembly approach, in which the 3′ or 5′ end maleimide-derivatized oligodeoxynucleotides are conjugated to albumin cysteine at position 34 (cys34) and annealed with complementary strands to allow single site-specific protein modification with functionalized ds oligodeoxynucleotides. Electrophoretic gel shift assays demonstrated successful annealing of complementary strands bearing Atto488, 6-carboxyfluorescein (6-FAM), or a factor IXa aptamer to the albumin-oligodeoxynucleotide conjugate. A fluorometric factor IXa activity assay showed retained aptamer inhibitory activity upon assembly with the albumin and completely blocked factor IXa at a concentration of 100 nM for 2 hr. The assembled construct exhibited stability in serum-containing buffer and FcRn engagement that could be increased using an albumin variant engineered for higher FcRn affinity. This work presents a novel albumin-oligodeoxynucleotide assembly technology platform that offers potential combinatorial drug delivery and half-life extension applications.

Original languageEnglish
JournalMolecular Therapy - Nucleic Acids
Volume9
Pages (from-to)284-293
Number of pages10
ISSN2162-2531
DOIs
Publication statusPublished - 15 Dec 2017

Keywords

  • albumin
  • anticoagulant
  • aptamer
  • covalent conjugation
  • cysteine 34
  • drug delivery
  • factor IXa
  • half-life extension
  • neonatal Fc receptor
  • oligodeoxynucleotides

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