title: Protection of erythrocytes from human complement-mediated lysis by membrane-targeted recombinant soluble CD59: a new approach to PNH therapy.
abstract: Paroxysmal nocturnal hemoglobinuria (PNH) results from the expansion of a hematopoietic clone that is deficient in glycosylphosphatidylinositol-anchored molecules. PNH is characterized by chronic hemolysis with acute exacerbations due to the uncontrolled activity of complement on PNH cells, which lack the inhibitor of homologous complement, CD59. Symptoms include severe fatigue, hemoglobinuria, esophageal spasm, erectile dysfunction, and thrombosis. We report the use of a novel synthetically modified recombinant human CD59, rhCD59-P, a soluble protein that attaches to cell membranes. In vitro treatment of PNH erythrocytes with rhCD59-P resulted in levels of CD59 equivalent to normal erythrocytes and effectively protected erythrocytes from complement-mediated hemolysis. The administration of rhCD59-P to CD1 mice resulted in levels of CD59 on erythrocytes, which protected them from complement-mediated lysis. Thus, rhCD59-P corrects the CD59 deficiency in vitro and can bind to erythrocytes in an in vivo murine model, protecting the cells from the activity of human complement, and represents a potential therapeutic strategy in PNH.
authors.affiliation: Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals National Health Service Trust, Algernon Firth Building, Great George Street, Leeds, United Kingdom, LS1 3EX. anitahill@nhs.net
authors.forename: Anita
authors.initials: A
authors.lastname: Hill
authors.forename: Simon H
authors.initials: SH
authors.lastname: Ridley
authors.forename: Dirk
authors.initials: D
authors.lastname: Esser
authors.forename: Rodney G
authors.initials: RG
authors.lastname: Oldroyd
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cullen
authors.forename: Paula
authors.initials: P
authors.lastname: Kareclas
authors.forename: Seán
authors.initials: S
authors.lastname: Gallagher
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Smith
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Richards
authors.forename: Jennifer
authors.initials: J
authors.lastname: White
authors.forename: Richard A G
authors.initials: RA
authors.lastname: Smith
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
mesh_terms: D000818:Animals; D018957:CD59 Antigens / Q000494:pharmacology* / Q000627:therapeutic use; D003167:Complement Activation / Q000187:drug effects*; D003165:Complement System Proteins / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006457:Hemoglobinuria, Paroxysmal / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018957:CD59 Antigens; D011994:Recombinant Proteins; C051590:CD59 protein, human; D003165:Complement System Proteins