Complement-targeted therapy: development of C5- and C5a-targeted inhibition

Abstract

The complement system is a major effector of humoral immunity and natural immunity. The complement system has three independent pathways of complement activation: a classical pathway, an alternative pathway, and a lectin pathway. These pathways converge to a common pathway that activates C3. This pathway also leads to the formation of various bioactive molecules such as C5a and the formation of membrane attack complex on the surface of target cells. In the past, the only preparations with anti-complementary action were C1 inhibitors (C1-INH), but an anti-C5 monoclonal antibody (eculizumab) appeared a few years ago, and this antibody has yielded encouraging results. In addition, a C5a receptor (C5aR) antagonist is in the clinical trial phase, and this antagonist should also prove efficacious. Anti-complement agents have garnered attention as a new treatment strategy for refractory inflammatory diseases.

Keywords: C5; C5a; C5a receptor; Complement; Membrane attack complex.

Fig. 1

Complement activation. Three pathways, i.e., classical, lectin, and alternative pathways, are independently activated to form C3 convertase. The activation of this cascade culminates in the generation of various fragments derived from complement proteins and the formation of membrane attack complex (MAC). The former acts as potent mediators of inflammation by binding to their receptors on the cell surface, while the latter is comprised of C5b, C6, C7, C8, and multiple copies of C9 that generate lytic pores in cellular membranes

Fig. 2

Activation of C5 by C5 convertase leads to the generation of C5a and C5b. C5a binds to C5a receptor and mediates various biological activities. C5b initiates the formation of MAC, which lyses cells as well as triggers inflammation