title: Considerations for the Characterization and Interpretation of Results Related to Alternative Complement Activation in Monkeys Associated with Oligonucleotide-Based Therapeutics.
abstract: This article provides an overview of the discussions held by the Immunomodulatory Subcommittee of the Oligonucleotide Safety Working Group on complement activation induced by oligonucleotides, most notably the phosphorothioate-containing oligonucleotides. Alternative complement pathway activation in monkeys is a common effect of single-stranded phosphorothioate backbone oligonucleotides in toxicology studies. This article discusses the mechanism for activation, general investigational strategy, and the impact of various chemical modifications. The goal is to provide the best practice approach to characterizing this effect, understanding the implication of the species specificity, and the interpretation of clinical relevance.
authors.affiliation: 1 Preclinical Development, Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
authors.affiliation: 2 Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University , Montreal, Canada .
authors.forename: Rosanne
authors.initials: R
authors.lastname: Seguin
authors.affiliation: 3 Access BIO , Boyce, Virginia.
authors.forename: Joy
authors.initials: J
authors.lastname: Cavagnaro
authors.affiliation: 4 Berman Consulting , Wayland, Virginia.
authors.forename: Cindy
authors.initials: C
authors.lastname: Berman
authors.affiliation: 5 Tepper Nonclinical Consulting , San Carlos, California.
authors.forename: Jeff
authors.initials: J
authors.lastname: Tepper
authors.affiliation: 6 Preclinsight , Reno, Nevada.
authors.forename: Douglas
authors.initials: D
authors.lastname: Kornbrust
mesh_terms: D000818:Animals; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D000882:Haplorhini; D006801:Humans; D054735:Phosphorothioate Oligonucleotides / Q000009:adverse effects* / Q000627:therapeutic use; D013045:Species Specificity
chemical_list: D054735:Phosphorothioate Oligonucleotides