C3 Glomerulopathy: Novel Treatment Paradigms

Abstract

C3 glomerulopathy (C3G) is diagnosed by kidney biopsy, with immunofluorescence showing isolated or dominant C3 staining, indicating hyperactivity of the alternative complement pathway as the key driver of glomerular injury. Therefore, the lesion is defined by its complement-mediated pathogenesis as much as its histological pattern. As a bevy of complement-targeting agents are moving through development and clinical trials, we review the evolution in treatment paradigms for C3G. Here we survey the limited efficacy of noncomplement targeting therapy before focusing on the work being done on targeting various components of the complement cascade in aiming to provide disease-specific therapy.

Keywords: complement; glomerulonephritis.

Figure 1

Complement-directed drugs for C3G and their targets in the complement cascade. Pegcetacoplan inhibits the binding of C3 to C3bBb and thus the formation of C5 convertase. ARO-C3 reduces hepatic production of C3. Iptacopan and NM8074 inhibit the enzymatic activity of factor B. Danicopan inhibits factor D and thus the cleavage of factor B. KP104 is a dual drug that has a factor H component, inhibiting the activity of C3 convertase C3bBb, and an anti-C5 antibody component that inhibits C5 cleavage. Eculizumab inhibits the cleavage of C5 and thus the release of C5a and C5b. Avacopan inhibits the binding of C5a to its receptor C5aR1. Narsoplimab targets MASP2, inhibiting the cleavage of C4 and C2 in the lectin pathway. MASP1, mannose-binding lectin associated serine protease 1; MASP2, mannose-binding lectin associated serine protease 2; MBL, mannose-binding lectin; FB, factor B; FD, factor D; C5aR, C5a receptor 1; MAC, membrane attack complex. ⚡Proteolytic cleavage.