An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications

Matthias Kuhlmann, Jonas B R Hamming, Anders Voldum, Georgia Tsakiridou, Maja T Larsen, Julie S Schmøkel, Emil Sohn, Konrad Bienk, David Schaffert, Esben S Sørensen, Jesper Wengel, Daniel M Dupont, Kenneth A Howard

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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.

TidsskriftMolecular Therapy - Nucleic Acids
Sider (fra-til)284-293
StatusUdgivet - 2017



Kuhlmann, M., Hamming, J. B. R., Voldum, A., Tsakiridou, G., Larsen, M. T., Schmøkel, J. S., Sohn, E., Bienk, K., Schaffert, D., Sørensen, E. S., Wengel, J., Dupont, D. M., & Howard, K. A. (2017). An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications. Molecular Therapy - Nucleic Acids, 9, 284-293.