Correlation of toxicity and pharmacokinetic properties of a phosphorothioate oligonucleotide designed to inhibit ICAM-1

Citation
Sp. Henry et al., Correlation of toxicity and pharmacokinetic properties of a phosphorothioate oligonucleotide designed to inhibit ICAM-1, TOX PATHOL, 27(1), 1999, pp. 95-100
Citations number
35
Categorie Soggetti
Pharmacology & Toxicology
Journal title
TOXICOLOGIC PATHOLOGY
ISSN journal
01926233 → ACNP
Volume
27
Issue
1
Year of publication
1999
Pages
95 - 100
Database
ISI
SICI code
0192-6233(199901/02)27:1<95:COTAPP>2.0.ZU;2-E
Abstract
ISIS 2302 is a phosphorothioate oligodeoxynucleotide with a sequence comple mentary to the mRNA of human intercellular adhesion molecule 1 (ICAM-1). Hy bridization of ISIS 2302 to the mRNA inhibits expression of the ICAM-1 prot ein in response to inflammatory stimuli. A murine active antisense oligonuc leotide, ISIS 3082, has been used for in vivo pharmacology studies and has anti-inflammatory activity in models of organ transplant rejection, ulcerat ive colitis, and collagen-induced arthritis at doses ranging from 0.03 to 5 mg/kg. The safety assessment for ISIS 2302 includes general toxicity studi es up to 6 mo in duration in mice and monkeys, genetic toxicity studies, an d reproductive/fertility studies. ISIS 3082 was examined in parallel with I SIS 2302 in mouse toxicity and reproductive studies. The toxicities observe d following systemic administration of ISIS 2302 and ISIS 3082 were similar and consistent with those observed for other compounds in this chemical cl ass and, therefore, are independent of the suppression of ICAM-1 expression . Toxicokinetic evaluation demonstrated that toxicities occurred in organs containing the highest concentrations of ISIS 2302. Evidence of immune stim ulation, including dose-dependent splenomegaly, lymphoid hyperplasia, and m ultiorgan mixed mononuclear cell infiltrates, was the most common finding i n rodent studies. Monkeys were much less sensitive than mice to immune stim ulation. Kidney contained the highest concentrations of ISIS 2302. Morpholo gic changes observed in kidney included atrophic and regenerative changes i n proximal tubular epithelium; however, there was no evidence of functional abnormalities. Additional histologic changes noted in proximal tubular epi thelium included basophilic granules, which were reflective of oligonucleot ide distribution and uptake in these cells. Liver also contained high conce ntrations of oligonucleotide, which were associated with Kupffer cell hyper trophy in mice. Changes in serum transaminases, cholesterol, and triglyceri des were reflective of hepatic alterations. In monkeys, high concentrations of oligonucleotide caused a transient increase in clotting times and activ ation of the alternative complement pathway. All toxicities associated with ISIS 2302 were reversible and occurred at doses well above those required for pharmacologic activity or currently used in clinical trials. In additio n, there has been no evidence of genetic toxicity associated with ISIS 2302 , and no changes in reproductive performance, fertility, or fetal developme nt have been noted in animals treated with ISIS 2302 or ISIS 3082.