title: A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement.
abstract: The clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH) is chronic intravascular hemolysis that is a consequence of unregulated activation of the alternative pathway of complement (APC). Intravascular hemolysis can be inhibited in patients by treatment with eculizumab, a monoclonal antibody that binds complement C5 thereby preventing formation of the cytolytic membrane attack complex of complement. However, in essentially all patients treated with eculizumab, persistent anemia, reticulocytosis, and biochemical evidence of hemolysis are observed; and in a significant proportion, their PNH erythrocytes become opsonized with complement C3. These observations suggest that PNH patients treated with eculizumab are left with clinically significant immune-mediated hemolytic anemia because the antibody does not block APC activation. With a goal of improving PNH therapy, we characterized the activity of anti-C3b/iC3b monoclonal antibody 3E7 in an in vitro model of APC-mediated hemolysis. We show that 3E7 and its chimeric-deimmunized derivative H17 block both hemolysis and C3 deposition on PNH erythrocytes. The antibody is specific for the APC C3/C5 convertase because classical pathway-mediated hemolysis is unaffected by 3E7/H17. These findings suggest an approach to PNH treatment in which both intravascular and extravascular hemolysis can be inhibited while preserving important immune functions of the classical pathway of complement.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Lindorfer
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Pawluczkowycz
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Peek
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hickman
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Taylor
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Parker
mesh_terms: D000143:Acids; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000918:Antibody Specificity / Q000187:drug effects*; D003176:Complement C3 / Q000276:immunology*; D003182:Complement C5 / Q000172:deficiency; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006457:Hemoglobinuria, Paroxysmal / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control*; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D018448:Models, Immunological; D011485:Protein Binding / Q000187:drug effects
chemical_list: D000143:Acids; D000911:Antibodies, Monoclonal; D003176:Complement C3; D003182:Complement C5