title: Plasma protein binding of an antisense oligonucleotide targeting human ICAM-1 (ISIS 2302).
abstract: 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.
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA 92008, USA. twatanab@isisph.com
authors.forename: Tanya A
authors.initials: TA
authors.lastname: Watanabe
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Levin
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D051379:Mice; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics*; D054735:Phosphorothioate Oligonucleotides; D051381:Rats; D013873:Thionucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014462:Ultrafiltration
chemical_list: D001798:Blood Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D013873:Thionucleotides; D018799:Intercellular Adhesion Molecule-1; C089753:alicaforsen