Complement blockade with a C1 esterase inhibitor in paroxysmal nocturnal hemoglobinuria

Amy Dezern, Marc Uknis, Xuan Yuan, Galina L. Mukhina, Juan Varela, JoAnne Saye, Jeffrey Pu, Robert A Brodsky

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)857-861
Number of pages5
JournalExperimental Hematology
Volume42
Issue number10
DOIs
StatePublished - Oct 1 2014

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Complement C1 Inhibitor Protein
Paroxysmal Hemoglobinuria
Hemolysis
Alternative Complement Pathway
Complement Inactivating Agents
Erythrocytes
Classical Complement Pathway
Mannose-Binding Lectin
Complement Activation
Hemolytic Anemia
Serine Proteases
Hematopoietic Stem Cells
Lectins
Blood Proteins
Thrombosis
Bone Marrow
Therapeutics
Serum
eculizumab

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

Cite this

Complement blockade with a C1 esterase inhibitor in paroxysmal nocturnal hemoglobinuria. / Dezern, Amy; Uknis, Marc; Yuan, Xuan; Mukhina, Galina L.; Varela, Juan; Saye, JoAnne; Pu, Jeffrey; Brodsky, Robert A.

In: Experimental Hematology, Vol. 42, No. 10, 01.10.2014, p. 857-861.

Research output: Contribution to journalArticle

Dezern, Amy ; Uknis, Marc ; Yuan, Xuan ; Mukhina, Galina L. ; Varela, Juan ; Saye, JoAnne ; Pu, Jeffrey ; Brodsky, Robert A. / Complement blockade with a C1 esterase inhibitor in paroxysmal nocturnal hemoglobinuria. In: Experimental Hematology. 2014 ; Vol. 42, No. 10. pp. 857-861.
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