title: Complement blockade with a C1 esterase inhibitor in paroxysmal nocturnal hemoglobinuria.
abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, hematopoietic stem cell disorder that manifests with a complement-mediated hemolytic anemia, bone marrow failure, and a propensity for thrombosis. These patients experience both intra- and extravascular hemolysis in the context of underlying complement activation. Currently eculizumab effectively blocks the intravascular hemolysis PNH. There remains an unmet clinical need for a complement inhibitor with activity early in the complement cascade to block complement at the classical and alternative pathways. C1 esterase inhibitor (C1INH) is an endogenous human plasma protein that has broad inhibitory activity in the complement pathway through inhibition of the classical pathway by binding C1r and C1s and inhibits the mannose-binding lectin-associated serine proteases in the lectin pathway. In this study, we show that commercially available plasma derived C1INH prevents lysis induced by the alternative complement pathway of PNH erythrocytes in human serum. Importantly, C1INH was able to block the accumulation of C3 degradation products on CD55 deficient erythrocytes from PNH patient on eculizumab therapy. This could suggest a role for inhibition of earlier phases of the complement cascade than that currently inhibited by eculizumab for incomplete or nonresponders to that therapy.
authors.affiliation: The Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA; Division of Hematology, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address: adezern1@jhmi.edu.
authors.forename: Amy E
authors.initials: AE
authors.lastname: DeZern
authors.affiliation: ViroPharma, Inc., Exton, PA, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Uknis
authors.affiliation: Division of Hematology, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Division of Hematology, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Galina L
authors.initials: GL
authors.lastname: Mukhina
authors.affiliation: Division of Hematology, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Varela
authors.affiliation: ViroPharma, Inc., Exton, PA, USA.
authors.forename: JoAnne
authors.initials: J
authors.lastname: Saye
authors.affiliation: Division of Hematology, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Pu
authors.affiliation: The Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA; Division of Hematology, Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address: brodsro@jhmi.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D018958:CD55 Antigens / Q000097:blood; D018957:CD59 Antigens / Q000097:blood; D050718:Complement C1 Inhibitor Protein / Q000494:pharmacology*; D003176:Complement C3 / Q000378:metabolism; D003182:Complement C5 / Q000037:antagonists & inhibitors; D003170:Complement Pathway, Alternative / Q000502:physiology; D003171:Complement Pathway, Classical / Q000187:drug effects*; D037582:Complement Pathway, Mannose-Binding Lectin / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018958:CD55 Antigens; D018957:CD59 Antigens; D050718:Complement C1 Inhibitor Protein; D003176:Complement C3; D003182:Complement C5; C051590:CD59 protein, human; C481642:eculizumab