In vivo characterization and therapeutic efficacy of a C5-specific inhibitor from the soft tick Ornithodoros moubata.
The involvement of complement (C) in inflammatory diseases has driven the search for agents capable of inhibiting dysregulated complement activation. Many of these reagents inhibit the C3 convertases during the early stages of the cascade. However, a drawback of total systemic C inhibition, particularly in longterm treatment of chronic disease, is potentiation of infection and immune complex disease due to an inability to opsonize complexes and foreign cells and to lyse pathogens. Recent identification of a C5-binding protein in the salivary gland of the soft tick Ornithodoros moubata has enabled development of a terminal pathway-specific reagent, OmCI, with potential to ameliorate disease while leaving key physiological processes unaffected. Here we demonstrated that OmCI has broad cross-species activity. When given intravenously to rodents, OmCI totally ablated complement hemolytic activity, which gradually restored as C5 was resynthesized. The circulating half-life of OmCI was 30 h, demonstrating a much slower clearance than other small, biological agents. Using C5-sufficient and C5-deficient mice we showed that prolonged half-life was due to binding to plasma C5. Surface plasmon resonance analysis of C5 binding to OmCI confirmed a high binding affinity with a slow dissociation rate. OmCI was effective in preventing experimental autoimmune myasthenia gravis induced by passive transfer in normal Lewis rats. OmCI ablated clinical disease, reduced C3 and C9 deposition at the neuro-muscular junction, and effected a marked reduction in cellular infiltration at this site. These data offer exciting prospects for targeted treatment of complement-mediated diseases without the detrimental inhibition of the opsonic roles of complement.
Hepburn
Natalie J
NJ
Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom.
Williams
Anwen S
AS
Nunn
Miles A
MA
Chamberlain-Banoub
Jayne C
JC
Hamer
John
J
Morgan
B Paul
BP
Harris
Claire L
CL
D000818:Animals; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D003165:Complement System Proteins / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D009157:Myasthenia Gravis / Q000378:metabolism; D026861:Ornithodoros; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000737:chemistry; D012469:Salivary Glands / Q000378:metabolism; D020349:Surface Plasmon Resonance
D003182:Complement C5; D011994:Recombinant Proteins; D003165:Complement System Proteins