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Inhibition of heparin/protamine complex-induced complement activation by Compstatin in baboons
A M Soulika1, M M Khan, T Hattori
1Department of Pathology and Laboratory Medicine School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA.
Insights
Compstatin effectively prevented complement activation during cardiac surgery in baboons without adverse effects. This peptide inhibitor shows promise for clinical use and oral drug development.
Area of Science:
- Immunology
- Cardiovascular Surgery
- Pharmacology
Background:
- Complement activation is a key inflammatory response after cardiac surgery and cardiopulmonary bypass.
- This activation contributes to postoperative organ dysfunction, fluid accumulation, and patient morbidity.
- Heparin-protamine complexes formed during extracorporeal circulation trigger complement system activation.
Purpose of the Study:
- To evaluate the efficacy of Compstatin, a novel peptide inhibitor, in preventing complement activation induced by heparin and protamine.
- To assess the safety and effectiveness of Compstatin in a preclinical primate model relevant to human physiology.
Main Methods:
- The study utilized baboons, chosen for Compstatin's binding to baboon C3 and resistance to proteolytic cleavage in their blood.
- Various doses and administration regimens of Compstatin were tested to determine optimal inhibition.
- Compstatin's effects on heparin/protamine-induced complement activation were measured in vivo, alongside hemodynamic parameters.
Main Results:
- Compstatin achieved complete inhibition of complement activation at a total dose of 21 mg/kg, administered via bolus and infusion.
- No adverse effects on heart rate or systemic, central venous, and pulmonary arterial pressures were observed.
- The study demonstrated Compstatin's safety and efficacy in preventing complement activation in a relevant animal model.
Conclusions:
- Compstatin is a safe and effective complement inhibitor with potential for clinical application in cardiac surgery.
- Compstatin can prevent complement activation during and after cardiopulmonary bypass procedures.
- The findings support Compstatin as a prototype for developing orally administered complement-inhibiting drugs.
Abstract:
Complement activation products are major components of the inflammatory response induced by cardiac surgery and cardiopulmonary bypass which contribute to postoperative organ dysfunction, fluid accumulation, and morbidity. Activation of the complement system occurs during extracorporeal circulation, during reperfusion of ischemic tissue, and after the formation of heparin-protamine complexes. In this study we examine the efficacy of Compstatin, a recently discovered peptide inhibitor of complement, in preventing heparin/protamine-induced complement activation in baboons. The study was performed in baboons because Compstatin binds to baboon C3 and is resistant to proteolytic cleavage in baboon blood (similar to humans); Compstatin inhibits only the activation of primates' complement system. After testing various doses and administration regimens, Compstatin produced complete inhibition at a total dose of 21 mg/kg when given as a combination of bolus injection and infusion. Compstatin completely inhibited in vivo heparin/protamine-induced complement activation without adverse effects on heart rate or systemic arterial, central venous, and pulmonary arterial pressures. This study indicates that Compstatin is a safe and effective complement inhibitor that has the potential to prevent complement activation during and after clinical cardiac surgery. Furthermore, Compstatin can serve as the prototype for designing an orally administrated drug.
