title: Effects of Repeated Complement Activation Associated with Chronic Treatment of Cynomolgus Monkeys with 2'-O-Methoxyethyl Modified Antisense Oligonucleotide.
abstract: The effects of repeated complement activation in cynomolgus monkeys after chronic antisense oligonucleotide (ASO) treatment were evaluated by using ISIS 104838, a representative 2'-O-methoxyethyl (2'-MOE) modified ASO. The treatment was up to 9 months with a total weekly dose of 30 mg/kg, given either as daily [4.3 mg/kg/day, subcutaneous (s.c.) injection] or once weekly [30 mg/kg, either as s.c. injection or 30-min intravenous (i.v.) infusion]. Acute elevations of complement split products (Bb and C3a) and a transient decrease in C3 occurred after the first dose and were drug plasma concentration dependent. However, with repeated complement activation after chronic ASO treatment, there were progressive increases in basal (predose) levels of Bb and C3a, and a sustained C3 reduction in all treated groups. There was also a progressive increase in C3d-bound circulating immune complex (CIC) that was considered secondary to the C3 depletion. Evidence of vascular inflammation was observed, mostly in the liver, kidney, and heart, and correlated with severe C3 depletion and increases in plasma IgG and IgM. Vascular inflammation was accompanied by increased C3 and IgM immunereactivity in the affected vasculatures and endothelial activation markers in serum. In summary, repeated complement activations in monkeys lead to a sustained decrease in circulating C3 over time. The concomitantly increased inflammatory signals and decreased CIC clearance due to impairment of complement function may lead to vascular inflammation after chronic ASO treatment in monkeys. However, based on the known sensitivity of monkeys to ASO-induced complement activation, these findings have limited relevance to humans.
authors.affiliation: 1 Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors.forename: Lijiang
authors.initials: L
authors.lastname: Shen
authors.affiliation: 1 Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelhardt
authors.affiliation: 1 Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.affiliation: 2 SNBL, USA, Ltd. , Everett, Washington.
authors.forename: Jenna
authors.initials: J
authors.lastname: Yee
authors.affiliation: 2 SNBL, USA, Ltd. , Everett, Washington.
authors.forename: Rie
authors.initials: R
authors.lastname: Kikkawa
authors.affiliation: 1 Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors.forename: John
authors.initials: J
authors.lastname: Matson
authors.affiliation: 1 Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors.forename: Bryan
authors.initials: B
authors.lastname: Tayefeh
authors.affiliation: 1 Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors.forename: Todd
authors.initials: T
authors.lastname: Machemer
authors.affiliation: 3 National Jewish Health , Denver, Colorado.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Giclas
authors.affiliation: 1 Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008252:Macaca fascicularis; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry; D054735:Phosphorothioate Oligonucleotides / Q000008:administration & dosage* / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C464616:ISIS104838; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D014409:Tumor Necrosis Factor-alpha