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Complement biomarker responses to factor B and C3 inhibition in C3 glomerulopathy
Abstract   Open access   Peer reviewed

Complement biomarker responses to factor B and C3 inhibition in C3 glomerulopathy

Kameron Kruger, Anna Carmen, Dingwu Shao, Carla M. Nester, Richard J.H. Smith and Yuzhou Zhang
Immunobiology (1979), Vol.230(4), 153012
07/2025
DOI: 10.1016/j.imbio.2025.153012
url
https://doi.org/10.1016/j.imbio.2025.153012View
Published (Version of record) Open Access

Abstract

C3 glomerulopathy (C3G) is a rare renal disorder characterized by complement dysregulation of the alternative pathway (AP). Emerging AP inhibitors include: (1) iptacopan, an oral factor B inhibitor that selectively binds to the enzymatic center of factor B, blocking its activity and preventing downstream complement activation; and (2) pegcetacoplan, a targeted inhibitor of C3/C3b that prevents the cleavage of C3 and subsequent formation of the C3 and C5 convertases. While both inhibitors have demonstrated clinical efficacy in reducing proteinuria and stabilizing renal function, their pharmacodynamic effects on complement biomarkers remain incompletely characterized. We evaluated complement biomarker profiles in 14 C3G patients treated with iptacopan (n = 6; age 19–67 years) or pegcetacoplan (n = 8; age 14–36 years). Serum and plasma samples collected before and after treatment were analyzed using a comprehensive in-house complement biomarker panel to monitor longitudinal changes. Both iptacopan and pegcetacoplan effectively inhibited AP activation, as evidenced by suppression of AP-specific activation assays and reductions in complement activation fragments (C3a, C3d, and Bb). These changes indicate complement inhibition at the level of the C3 convertase. Consequently, plasma C3 levels increased in both treatment groups, though the magnitude of increase differed: iptacopan-treated patients generally reached low-normal C3 (normal reference range: 90–180 mg/dL), whereas pegcetacoplan-treated patients often exhibited markedly elevated plasma C3, substantially exceeding normal limits. Additionally, highly elevated properdin levels were observed in pegcetacoplan-treated patients but not in those treated with iptacopan. Both therapies also reduced C5 convertase activity, as demonstrated by normalization of plasma C5 and soluble C5b-9. Notably, neither drug impacted circulating autoantibody levels. Together, these findings highlight distinct pharmacodynamic profiles and illustrate the dynamic complexity of complement regulation in C3G. Iptacopan and pegcetacoplan robustly inhibit AP activation, offering promising therapeutic strategies for C3G. Larger longitudinal studies are needed to define biomarker predictors of treatment response and guide personalized complement-directed therapy. Supported in part by National Institutes of HealthR01 DK110023.

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