Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery

Abstract

Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk. Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G). Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials.

Keywords: AMY-101; C3 glomerulopathy; C3 inhibitors; anti-C5 therapy; clinical efficacy; compstatin.

Conflict of interest statement

Conflicts of interest

J.D.L., D.R. and R.J.S. are the inventors of patents and/or patent applications that describe complement inhibitors and/or their use for therapeutic purposes. J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for clinical applications. The remaining authors declare no competing financial interests.

Published by Elsevier Ltd.

Figures

Figure I. An Overview of the Complement Activation Cascade

A schematic representation of the wide spectrum of protein-protein interactions, multi-protein assemblies and effector functions mediated by complement components in the vasculature, on the surface, or in the inner compartments of targeted cells. Key interactions are discussed in greater detail in the text. Abbreviations: MBL, mannose-binding lectin; MASPs, mannose-binding lectin associated proteases; FP, properdin; FB, factor B; FD, factor D; AP, alternative pathway; FH, factor H; CFHRs, complement factor H-related proteins; MAC, membrane attack complex; C5aR1, C5a receptor 1; C5aR2, C5a receptor 2; CTSL, cathepsin-L.

Figure 1. C3-targeted Intervention Intercepts Multiple Proinflammatory Effectors of Renal Pathology

Panel A: Through its dense network of capillaries, the glomerulus serves as the basic blood filtration unit of the kidney. Therefore proper renal function relies largely on the structural and functional integrity of this specialized ‘unit’. Mesangial cells form the so-called mesangium, a stalk-like structure of mesenchymal origin that serves as a support for the glomerular vasculature and also contributes to the blood filtration process, thereby aiding urine formation (panel A). Podocytes are specialized perivascular epithelial cells extending long processes (foot processes, or pedicels) that wrap around glomerular capillaries and contribute to blood ultrafiltration by creating appropriate filtration slits (panel A). Capillary endothelial cells, podocytes and the glomerular basement membrane (GBM) altogether form the glomerular filtration barrier. (Panel B): A derailed complement response can target multiple anatomical sites and structures within the kidney glomerulus, such as the glomerular basement membrane (GBM), the mesangium, and the capillary endothelial cell wall. Excessive complement activation contributes to renal pathology in several clinical indications, including microangiopathies (atypical hemolytic uremic syndrome [aHUS]) and C3 glomerulopathy (C3G). These clinical disorders, although manifested in distinct anatomical compartments of the kidney, share a common profile of complement-specific genetic perturbations and serum biomarkers. Most of these genetic or acquired alterations affect the functionality of complement regulators that normally control autologous complement responses, protecting host surfaces such as the GBM from inflammatory damage (right panel, top schematic). In C3G, complement dysregulation results in autologous complement attack on the GBM and is tightly linked to the formation of electron dense deposits and impaired renal function (left panel). This deregulated response can be driven by genetic factors or autoantibodies (i.e., C3 nephritic factors, C3Nefs) that stabilize the enzymatic complex that cleaves C3 into its bioactive fragments C3a and C3b (panel B). Factor H is a fluid-phase regulator of the alternative pathway (AP) that circulates in the plasma and can attach to host surfaces through high-affinity binding to carbohydrate moieties (e.g., GAGs) (right panel, top schematic). Genetic variations in FH leading to partial or complete loss of its ability to regulate C3 convertase in the fluid phase and on host surfaces have been linked to C3G. Impaired FH function can lead to uncontrolled C3 activation and persistent C3b deposition in the GBM via AP amplification (right panel, middle). Recent studies have shown that targeted C3 inhibition can restore complement regulation in C3G, attenuating multiple drivers of inflammatory damage (right panel, bottom schematic). C3-based inhibitors offer broad control over the detrimental consequences of complement activation in the kidney by simultaneously blocking the generation of multiple effectors (e.g., C3a, C5a, MAC). Abbreviations: iC3b, inactive C3; FH, factor H; CFHRs, complement FH-related proteins; EC, glomerular endothelial cell; GBM, glomerular basement membrane; C3Nef, C3 nephritic factor.