Complement blockade with a C1 esterase inhibitor in paroxysmal nocturnal hemoglobinuria

• Published in: Experimental hematology Vol. 42; no. 10; pp. 857 - 861.e1
• Main Authors: DeZern, Amy E, Uknis, Marc, Yuan, Xuan, Mukhina, Galina L, Varela, Juan, Saye, JoAnne, Pu, Jeffrey, Brodsky, Robert A
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.10.2014
• Subjects: Adult; Advanced Basic Science; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; CD55 Antigens - blood; CD59 Antigens - blood; Complement C1 Inhibitor Protein - pharmacology; Complement C3 - metabolism; Complement C5 - antagonists & inhibitors; Complement Pathway, Alternative - physiology; Complement Pathway, Classical - drug effects; Complement Pathway, Mannose-Binding Lectin - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance; Erythrocyte Membrane - drug effects; Erythrocyte Membrane - immunology; Erythrocyte Membrane - metabolism; Female; Hematology, Oncology and Palliative Medicine; Hemoglobinuria, Paroxysmal - blood; Hemoglobinuria, Paroxysmal - drug therapy; Hemoglobinuria, Paroxysmal - immunology; Humans; Male; Middle Aged; Young Adult
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2014.06.007

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.