title: Efficacy of Targeted Complement Inhibition in Experimental C3 Glomerulopathy.
abstract: C3 glomerulopathy refers to renal disorders characterized by abnormal accumulation of C3 within the kidney, commonly along the glomerular basement membrane (GBM). C3 glomerulopathy is associated with complement alternative pathway dysregulation, which includes functional defects in complement regulator factor H (FH). There is no effective treatment for C3 glomerulopathy. We investigated the efficacy of a recombinant mouse protein composed of domains from complement receptor 2 (CR2) and FH (CR2-FH) in two models of C3 glomerulopathy with either preexisting or triggered C3 deposition along the GBM. FH-deficient mice spontaneously develop renal pathology associated with abnormal C3 accumulation along the GBM and secondary plasma C3 deficiency. CR2-FH partially restored plasma C3 levels in FH-deficient mice 2 hours after intravenous injection. CR2-FH specifically targeted glomerular C3 deposits, reduced the linear C3 reactivity assessed with anti-C3 and anti-C3b/iC3b/C3c antibodies, and prevented further spontaneous accumulation of C3 fragments along the GBM. Reduction in glomerular C3d and C9/C5b-9 reactivity was observed after daily administration of CR2-FH for 1 week. In a second mouse model with combined deficiency of FH and complement factor I, CR2-FH prevented de novo C3 deposition along the GBM. These data show that CR2-FH protects the GBM from both spontaneous and triggered C3 deposition in vivo and indicate that this approach should be tested in C3 glomerulopathy.
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom; and.
authors.forename: Marieta M
authors.initials: MM
authors.lastname: Ruseva
authors.affiliation: Alexion Pharmaceuticals, Cheshire, Connecticut.
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
authors.affiliation: Alexion Pharmaceuticals, Cheshire, Connecticut.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Lasaro
authors.affiliation: Alexion Pharmaceuticals, Cheshire, Connecticut.
authors.forename: Keith
authors.initials: K
authors.lastname: Bouchard
authors.affiliation: Alexion Pharmaceuticals, Cheshire, Connecticut.
authors.forename: Susan
authors.initials: S
authors.lastname: Liu-Chen
authors.affiliation: Alexion Pharmaceuticals, Cheshire, Connecticut.
authors.forename: Fang
authors.initials: F
authors.lastname: Sun
authors.affiliation: Alexion Pharmaceuticals, Cheshire, Connecticut.
authors.forename: Zhao-Xue
authors.initials: ZX
authors.lastname: Yu
authors.affiliation: Alexion Pharmaceuticals, Cheshire, Connecticut.
authors.forename: Andre
authors.initials: A
authors.lastname: Marozsan
authors.affiliation: Alexion Pharmaceuticals, Cheshire, Connecticut.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom; and matthew.pickering@imperial.ac.uk.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D050533:Glomerular Basement Membrane / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000597269:CR2-fH protein; D003176:Complement C3; D011993:Recombinant Fusion Proteins
keywords: complement; glomerulopathy; therapy