Soluble Complement Regulators as Therapeutic Target

Soluble Complement Regulators as Therapeutic Target of Complement System Background

Because regulators of complement activation are natural modifiers of complement activities and prevent a host cell from being attacked by its own defense system, they have been considered for therapeutic use since the early stages of complement drug discovery. A first breakthrough was reached with the expression of a soluble form of complement receptor 1 (sCR1), This molecule featured both decay accelerator and cofactor activity and had a high potency in inhibiting both the classical and alternative pathways. sCR1 showed promising results in the treatment of I/R injury and various other conditions in experimental animal models. Based on these encouraging results, sCR1 was developed as a therapeutic (TP10; Avant Immunotherapeutics, Needham, MA, USA) for use after coronary artery bypass graft surgery. TP10 is expressed as a 240-kDa glycoprotein in Chinese hamster ovary cells, has a plasma half-life of ~55 hours and is safe and well-tolerated in both adult and infant patients. In a large placebo-controlled phase 2 trial, comprising 564 high-risk patients undergoing cardiac surgery, a single intravenous bolus of TP10 immediately before surgery was found to inhibit complement activation for up to 3 days postoperatively.

Soluble forms of MCP, DAF and CD59 have also been considered as therapeutic target. Whereas DAF and MCP each offer only a single regulatory activity, a recombinant chimera of their extracellular parts has been developed. The resulting sDAF-sMCP hybrid was initially named "complement activity blocker 2" (CAB-2; Xoma, Berkeley, CA, USA) but entered clinical trials with a new name and licensing partner (MLN-2222; Millennium, Cambridge, MA, USA). However, no further studies have been initiated recently. Like Mirococept/APT070, a membrane-tethering sCD59 has been developed by Inflazyme Pharmaceuticals. Paroxysmal nocturnal hemoglobinuria (PNH), is a rare, genetic, life-threatening blood disorder that leads to decreased expression of membrane-anchored proteins, including CD59 and DAF, on erythrocytes. Some experimental studies were recently performed to investigate its potential therapeutic usefulness as a treatment option for PNH. Therefore, substitution and membrane tethering of recombinant CD59 may develop into a promising therapy for PNH.

Soluble Complement Regulators as Therapeutic Target of Complement System

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Soluble Complement Regulators as Therapeutic Target of Complement System References

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