Complement activation is responsible for acute toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide.
The objective of this study was to define the role of complement activation in the acute and transient toxicities associated with administration of phosphorothioate oligonucleotides in monkeys. In the absence of complement inhibitor, complement activation blocker-2 (CAB-2), i.v. infusion of 20 mg/kg ISIS 2302 produced increases in the concentrations of the complement split products Bb and C5a (100- and 7-fold, respectively). Monkeys also experienced marked changes in bloodpressure (hypertension and hypotension), clinical signs of toxicity (lethargy and periorbital edema), fluctuations in circulating neutrophil counts, and elevations in serum cytokine levels (45-, 12-, and 4-fold increases in IL-6, MCP-1, and IL-12, respectively). Changes occurred at or near the end of infusion and returned to normal over time. One of the three animals died approximately 4 h following infusion of 20 mg/kg ISIS 2302 alone. In contrast, prior treatment with CAB-2 effectively blocked complement activation, as well as the ISIS 2302-induced hemodynamic and clinical responses. Importantly, plasma concentration of ISIS 2302 were unaffected by CAB-2 pretreatment. Thus, the protection afforded by CAB-2 was due to its inhibition of complement activation rather than to any impact on the disposition of ISIS 2302. These results clearly demonstrate the causal relationship between activation of the alternative complement pathway and the hemodynamic and clinical responses associated with rapid infusion of phosphorothioate oligonucleotides. Demonstration of this relationship underscores the importance of avoiding complement activation in patients to ensure the continued safe use of phosphorothioate oligodeoxynucleotides.
Henry
Scott P
SP
Toxicology and Pharmacokinetics Department, Isis Pharmaceuticals, Inc., 2292 Faraday Avenue, Carlsbad, CA 92008, USA. shenry@isisph.com
Beattie
Greg
G
Yeh
Grace
G
Chappel
Alfred
A
Giclas
Patricia
P
Mortari
Angela
A
Jagels
Mark A
MA
Kornbrust
Douglas J
DJ
Levin
Arthur A
AA
D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage / Q000494:pharmacology; D003167:Complement Activation / Q000187:drug effects*; D003170:Complement Pathway, Alternative / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D008253:Macaca mulatta / Q000276:immunology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D054735:Phosphorothioate Oligonucleotides; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013873:Thionucleotides / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D013997:Time Factors
D015703:Antigens, CD; D016207:Cytokines; D007166:Immunosuppressive Agents; D020319:Oligodeoxyribonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D011993:Recombinant Fusion Proteins; D013873:Thionucleotides; C410468:complement activation blocker 2, human; C089753:alicaforsen