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Trends Immunol. 2017 Jun;38(6):383-394. doi: 10.1016/j.it.2017.03.003. Epub 2017 Apr 14.

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

Author information

1
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Biodiagnostic Sciences and Technologies, Institute of Nuclear and Radiological Sciences and Technology, Energy, and Safety (INRASTES), National Center for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, 15310 Athens, Greece.
2
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
4
Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. Electronic address: richard-smith@uiowa.edu.
5
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: lambris@upenn.edu.

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

PMID:
28416449
PMCID:
PMC5447467
DOI:
10.1016/j.it.2017.03.003
[Indexed for MEDLINE]
Free PMC Article

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