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
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.