Complement and Complement Targeting Therapies in Glomerular Diseases

Abstract

The complement cascade is part of the innate immune system whose actions protect hosts from pathogens. Recent research shows complement involvement in a wide spectrum of renal disease pathogenesis including antibody-related glomerulopathies and non-antibody-mediated kidney diseases, such as C3 glomerular disease, atypical hemolytic uremic syndrome, and focal segmental glomerulosclerosis. A pivotal role in renal pathogenesis makes targeting complement activation an attractive therapeutic strategy. Over the last decade, a growing number of anti-complement agents have been developed; some are approved for clinical use and many others are in the pipeline. Herein, we review the pathways of complement activation and regulation, illustrate its role instigating or amplifying glomerular injury, and discuss the most promising novel complement-targeting therapies.

Keywords: C3 glomerulopathy; alternative complement pathway; complement; complement-targeting therapies; focal segmental glomerulosclerosis; hemolytic uremic syndrome.

Figure 1

Overview of the complement cascade and principal complement targeting molecules. Three pathways can initiate complement cascade: (1) The classical, (2) the mannose-binding lectin (MBL), and (3) the alternative pathway. They all converge on C3 convertases formation which continuously cleave C3; after they are activated, the C3 convertase from alternative pathway dominates within an amplification loop that sustains the production of C3b (circular arrow). The three C3 convertases associate with an additional C3b to form the C5 convertases, which cleave C5 into C5a + C5b. C5b fragments recruits C6, C7, C8, and multiple C9 molecules to generate the terminal membrane attack complex (MAC); MAC inserts pores into cell membranes to induce cell lysis or activation. Anaphilotoxins C3a and C5a through their G protein-coupled receptors C3aR and C5aR, respectively, can promote signaling, inflammation, chemotaxis of leukocytes, vasodilation, cytokine and chemokine release, and activation of adaptive immunity. Dotted black arrows: inhibitor function of a complement effector on its target. Red arrows emerging from balloons: inhibitor function of anti complement drug on its target (bold drugs’ names are the FDA approved ones). Full arrow: consequential interaction between complement fractions leads to the subsequent cascade step. Full bold arrow: final convergence of the three complement pathways on same final target. MBL: Mannose binding lectin; MASP: Mannose-binding lectin-associated serine protease; C4BP: C4 binding protein; C1-INH: C1 inhibitor; DAF: Decay accelerating factor; CR1: Surface complement receptor 1; MCP: Membrane cofactor protein; CD59: Protectin; fD: Factor D; fB: Factor B; fI: Factor I; fH: Factor H. Red balloons highlights complement target drugs’ points of action (see Table 1).