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A soluble chimeric complement inhibitory protein that possesses both decay-accelerating and factor I cofactor
P J Higgins1, J L Ko, R Lobell
1CytoMed, Inc., Cambridge, MA 02139, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|March 15, 1997
Summary
A novel chimeric protein, complement activation blocker-2 (CAB-2), effectively inhibits complement activation in vitro and in vivo. CAB-2 shows superior activity compared to existing complement inhibitors, suggesting therapeutic potential for complement-mediated diseases.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- The complement system is crucial for innate immunity but can cause tissue damage when overactivated.
- Existing complement inhibitors have limitations in efficacy and scope.
- Developing novel inhibitors targeting complement cascade is essential for treating inflammatory diseases.
Purpose of the Study:
- To create and characterize a novel chimeric protein, complement activation blocker-2 (CAB-2), with enhanced complement inhibitory activity.
- To evaluate the in vitro and in vivo efficacy of CAB-2 in blocking complement activation.
- To assess the pharmacokinetic properties of CAB-2.
Main Methods:
- Construction of a chimeric gene encoding human membrane cofactor protein (CD46) and decay-accelerating factor (CD55).
- Transfection into Chinese hamster ovary cells to produce soluble, glycosylated CAB-2.
- In vitro assays to determine C3/C5 convertase inactivation and cofactor activity.
- In vivo studies in guinea pigs (Arthus reaction, Forssman shock) and rats (pharmacokinetics).
Main Results:
- CAB-2 demonstrated potent inhibition of classical and alternative C3/C5 convertases in vitro.
- CAB-2 exhibited significantly greater specific activity against cell-associated convertases than individual components or their combination.
- In vivo studies confirmed CAB-2's ability to block complement activation, inhibiting Arthus reaction and Forssman shock.
- Pharmacokinetic studies in rats showed favorable biphasic disposition with a long terminal half-life (t1/2 beta of 8 hours).
Conclusions:
- CAB-2 is a potent, bifunctional complement inhibitor with superior activity compared to existing soluble inhibitors.
- CAB-2 effectively blocks complement activation in vivo, offering a promising therapeutic strategy.
- The favorable pharmacokinetic profile of CAB-2 supports its potential for treating acute human diseases driven by excessive complement activation.