Compstatin: A Complement Inhibitor on its Way to Clinical Application

Abstract

Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic. Tackling Complement at its CoreTherapeutic intervention in the human complement system has long been recognized as a promising strategy for the treatment of a series of ischemic, inflammatory and autoimmune diseases (Lambris and Holers 2000;Ricklin and Lambris 2007a). In principle, the large network of soluble and cell-surface-bound proteins, which builds the base of the complement cascade, offers a variety of potential drug targets. However, the quest for complement-specific therapeutics proved to be much more challenging than initially anticipated. With the therapeutic antibody eculizumab (Soliris ® , Alexion Pharmaceuticals, Inc.) against paroxysmal nocturnal hemoglobinuria, the first drug with proven complement connectivity has been marketed only recently (Ricklin and Lambris 2007a;Rother et al. 2007). A second complement-associated compound, purified C1 esterase inhibitor (C1-INH), is available as a therapeutic option for the treatment of hereditary angioedema in several countries. However, its mechanism of action may be closer related to the bradykinin-kallikrein than the complement cascade (Davis 2006). Strikingly, both drugs cover relatively rare diseases and have been developed with the aid of orphan drug regulations. Yet, for many of the more common inflammatory or autoimmune conditions there are no complement drugs on the market. Any extension of the current complement-specific therapeutic arsenal is therefore highly desired.Part of the problem in complement-directed drug discovery is the selection of the right target (Ricklin and Lambris 2007a activation is considered to be the most promising approach in many cases. On a molecular level, inhibition at the level of C3, including the C3 convertases, is of particular interest since both the amplification of all initiation pathways and the generatio...

Complement in age-related macular degeneration: a focus on function

“…At almost every step of all three pathways, there is crosstalk with proteins from other physiological pathways. 5,21 The alternative pathway is continuously activated by spontaneous hydrolysis of the internal thioester bond in C3 to form C3(H 2 0) ( Figure 1). This molecule, although not cleaved, can fulfil the same role as C3b in a C3 convertase.…”

“…Compstatin has been developed as a potential treatment that targets the complement system. 21 It is a peptide that is administered by intra-vitreal injection, and which binds to C3 protein and inhibits binding of the C3 molecule to the C3b in the C3 convertase. The injected material forms a gel that slowly releases the molecule over many months, therefore dosing intervals could be relatively long.…”

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

“…Therefore, compstatin is an ideal compound to inhibit classical, lectin as well as AP activation. 61 It has been tested in several animal models and shown to be an effective complement inhibitor. 62,63 Recently, Risitano and co-workers elegantly demonstrated that pegylated compstatin not only efficiently prevents lysis of PNH-RBCs, but also C3 deposition.…”

Complement—here, there and everywhere, but what about the transplanted organ?

“…In addition, a neutralising C5 antibody utilizing a different epitope to Eculizumab has also been developed known as 'Mubodina' however sepsis and the development of inflammatory disease are side effects that have limited clinical trials [134]. In contrast, Compstatin is a cyclic tridecapeptide C3 inhibitor function that continues to be promising in clinical trials as a treatment for age-related macular degeneration [135]. It binds C3 reversibly whilst inhibiting the convertase mediated cleavage of C3 to C3a and C3b affecting the classical and alternative pathways.…”

“…Anti-MASP-2 is a human monoclonal antibody that selectively inhibits MASP-2 thereby blocking the lectin pathway. There are ongoing clinical trials in aHUS and if successful this selective blockade may be associated with a lower infectious risk as the classical pathway would remain unaffected [135]. Previous murine models have shown a reduction in IR injury of the myocardium and gastrointestinal tract with blockade of MASP-2 [51].…”