Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery. Issue 6 (June 2017) - Mastellos, Dimitrios C.
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. Trends: Proteins of the complement cascade together form a key innate immune sensor that mediates immunosurveillance and tissue homeostasis through extensive crosstalk with other pattern recognition systems. However, deregulation of complement responses can fuel a vicious cycle of tissue injury and inflammation. C5 blockade has proven effective for treating some complement-mediated diseases, but it has also revealed new pathogenic mechanisms that remain unaddressed. C3G is a rare renal disorder driven by aberrant complement activation and dysregulation of complement responses on the glomerular basement membrane (GBM). Blockade of the central component C3 is emerging as a therapeutic modality for C3G. Assertions related to potential risks and complications during prolonged C3 intervention need to be replaced by evidence-based discovery and clinical data.