title: Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy.
abstract: 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.
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Dingwu
authors.initials: D
authors.lastname: Shao
authors.affiliation: Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Brieanna M
authors.initials: BM
authors.lastname: Hilkin
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Nester
authors.affiliation: Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. Electronic address: richard-smith@uiowa.edu.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003176:Complement C3 / Q000037:antagonists & inhibitors*; D050577:Complement C3-C5 Convertases / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology*; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy*; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy*; D006801:Humans; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011323:Primates; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012756:Sheep
chemical_list: D003176:Complement C3; D010456:Peptides, Cyclic; D011728:Pyridones; C111828:compstatin; C098211:1-(ethan-1-ol)-2-methyl-3-hydroxypyridin-4-one; D050577:Complement C3-C5 Convertases
keywords: C3 glomerulonephritis; C3 glomerulopathy; Complement dysregulation; Compstatin; Dense deposit disease