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Vol. 281, Issue 2, 810-816, 1997
Department of Toxicology, Isis Pharmaceuticals, Inc. (S.P.H, J.L.,
A.A.L.), Carlsbad, California,
National Jewish Medical & Research
Center (P.C.G.), Denver, Colorado,
University of Texas, Tyler (M.P.),
Tyler, Texas,
Huntington Life Sciences (C.A.), East Millstone, New
Jersey and
Sierra Biomedical, Inc. (D.J.K.), Sparks, Nevada.
Intravenous infusion of high doses of phosphorothioate oligonucleotides
in monkeys has been associated with transient alterations in
hematologic and hemodynamic parameters, which appear to be secondary to
complement activation. ISIS 2302, a phosphorothioate oligonucleotide
specific for human intracellular adhesion molecule-1, was used to
further characterize complement activation in monkeys. Complement
activation occurred selectively through the alternative pathway
resulting in increased plasma concentrations of the complement split
products Bb, C3a and C5a. Marked fluctuations in circulating neutrophil
counts and reductions in cardiac output were closely associated with
peak production of anaphylatoxins C3a and C5a. Changing both dose and
infusion duration revealed that complement activation is related to
plasma levels of oligonucleotide, and that there is a minimum threshold
concentration of approximately 50 µg/ml of ISIS 2302 that is required
to activate complement. Dose regimens in which plasma concentrations do
not exceed this threshold do not result in complement activation.
Further investigation reveals that plasma concentrations of a key
regulatory component of the alternative pathway, Factor H, were also
decreased after administration of ISIS 2302. Decreases in Factor H
levels are suggestive of a possible mechanism of complement activation.
Direct interaction between ISIS 2302 and Factor H was demonstrated in a
competition assay, where increasing concentrations of ISIS 2302 eluted
Factor H from a heparin-sepharose column. These data demonstrate a
clear correlation between plasma oligonucleotide concentrations and
complement activation. Interactions between ISIS 2302 and Factor H may
lead to activation of the alternative complement pathway.
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