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Published Online: 9 June 2006

Plasma Protein Binding of an Antisense Oligonucleotide Targeting Human ICAM-1 (ISIS 2302)

Publication: Oligonucleotides
Volume 16, Issue Number 2


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 α2-macroglobulin and had negligible binding to α1-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.

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Published In

cover image Oligonucleotides
Volume 16Issue Number 2Summer 2006
Pages: 169 - 180
PubMed: 16764540


Published online: 9 June 2006
Published in print: Summer 2006


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Dr. Tanya A. Watanabe
Isis Pharmaceuticals, Inc., Carlsbad, CA 92008.
Richard S. Geary
Isis Pharmaceuticals, Inc., Carlsbad, CA 92008.
Arthur A. Levin
Isis Pharmaceuticals, Inc., Carlsbad, CA 92008.

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