Journal article
Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy
Immunobiology (1979), Vol.220(8), pp.993-998
08/2015
DOI: 10.1016/j.imbio.2015.04.001
PMCID: PMC4510458
PMID: 25982307
Abstract
•C3 glomerulopathy (C3G) defines a group of untreatable ultra-rare renal diseases.•C3G is caused by dysregulation of the alternative complement pathway.•Nearly half of C3G patients progress to end stage renal failure within 10 years.•Cp40, a compstatin analog, inhibits complement by binding to C3 and C3b.•Cp40 may offer a novel and promising therapeutic option to C3G patients.
C3 glomerulopathy (C3G) defines a group of untreatable ultra-rare renal diseases caused by uncontrolled activation of the alternative complement pathway. Nearly half of patients progress to end stage renal failure within 10 years. Cp40, a second-generation compstatin analog in clinical development, is a 14 amino-acid cyclic peptide that selectively inhibits complement activation in humans and non-human primates by binding to C3 and C3b. We hypothesized that by targeting C3 Cp40 would provide an effective treatment for C3G. By investigating its effects in vitro using multiple assays of complement activity, we show that Cp40 prevents complement-mediated lysis of sheep erythrocytes in sera from C3G patients, prevents complement dysregulation in the presence of patient-derived autoantibodies to the C3 and C5 convertases, and prevents complement dysregulation associated with disease-causing genetic mutations. In aggregate, these data suggest that Cp40 may offer a novel and promising therapeutic option to C3G patients as a disease-specific, targeted therapy. As such, Cp40 could represent a major advance in the treatment of this disease.
Details
- Title: Subtitle
- Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy
- Creators
- Yuzhou Zhang - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USADingwu Shao - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USADaniel Ricklin - Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USABrieanna M Hilkin - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USACarla M Nester - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USAJohn D Lambris - Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USARichard J.H Smith - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Immunobiology (1979), Vol.220(8), pp.993-998
- DOI
- 10.1016/j.imbio.2015.04.001
- PMID
- 25982307
- PMCID
- PMC4510458
- NLM abbreviation
- Immunobiology
- ISSN
- 0171-2985
- eISSN
- 1878-3279
- Publisher
- Elsevier BV
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: AI068730, AI030040, EY020633, GM097747; name: European Community's Seventh Framework Programme, award: 602699
- Language
- English
- Date published
- 08/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984006483802771
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