Plasma protein binding of an antisense oligonucleotide targeting human ICAM-1 (ISIS 2302)

Oligonucleotides. 2006 Summer;16(2):169-80. doi: 10.1089/oli.2006.16.169.


In vitro ultrafiltration was used to determine the plasma protein-binding characteristics of phosphorothioate oligonucleotides (PS ODNs). Although there are binding data on multiple PS ODNs presented here, the focus of this research is on the protein-binding characteristics of ISIS 2302, a PS ODN targeting human intercellular adhesion molecule-1 (ICAM-1) mRNA, which is currently in clinical trials for the treatment of ulcerative colitis. ISIS 2302 was shown to be highly bound (> 97%) across species (mouse, rat, monkey, human), with the mouse having the least degree of binding. ISIS 2302 was highly bound to albumin and, to a lesser, extent alpha2-macroglobulin and had negligible binding to alpha1-acid glycoprotein. Ten shortened ODN metabolites (8, 10, and 12-19 nucleotides [nt] in length, truncated from the 3' end) were evaluated in human plasma. The degree of binding was reduced as the ODN metabolite length decreased. Three additional 20-nt (20-mer) PS ODNs (ISIS 3521, ISIS 2503, and ISIS 5132) of varying sequence but similar chemistry were evaluated. Although the tested PS ODNs were highly bound to plasma proteins, suggesting a commonality within the chemical class, these results suggested that the protein-binding characteristics in human plasma may be sequence dependent. Lastly, drug displacement studies with ISIS 2302 and other concomitant drugs with known protein-binding properties were conducted to provide information on potential drug interactions. Coadministered ISIS 2302 and other high-binding drugs evaluated in this study did not displace one another at supraclinical plasma concentrations and, thus, are not anticipated to cause any pharmacokinetic interaction in the clinic as a result of the displacement of binding to plasma proteins.

MeSH terms

  • Animals
  • Blood Proteins / metabolism*
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics*
  • Mice
  • Oligodeoxyribonucleotides, Antisense / administration & dosage
  • Oligodeoxyribonucleotides, Antisense / pharmacokinetics*
  • Phosphorothioate Oligonucleotides
  • Rats
  • Thionucleotides / administration & dosage
  • Thionucleotides / pharmacokinetics*
  • Ultrafiltration


  • Blood Proteins
  • Oligodeoxyribonucleotides, Antisense
  • Phosphorothioate Oligonucleotides
  • Thionucleotides
  • Intercellular Adhesion Molecule-1
  • alicaforsen