Soluble Complement Regulators as Therapeutic Target of Complement System

Soluble Complement Regulators as Therapeutic Target of Complement System

Other Complement Regulators of Complement System Related Products

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 References

1. Ricklin D, et al. (2007). Complement-targeted therapeutics. Nature biotechnology, 25(11), 1265-1275. 2. Holers V M. (2003). The complement system as a therapeutic target in autoimmunity. Clinical Immunology, 107(3), 140-151. 3. Makrides S C. (1998). Therapeutic inhibition of the complement system. Pharmacological Reviews, 50(1), 59-88.