The complement model disease paroxysmal nocturnal hemoglobinuria.
Complement system
Complement therapeutics
Danicopan
Eculizumab
Iptacoplan
PNH
Paroxysmal nocturnal hemoglobinuria
Pegcetacoplan
Ravulizumab
Journal
European journal of immunology
ISSN: 1521-4141
Titre abrégé: Eur J Immunol
Pays: Germany
ID NLM: 1273201
Informations de publication
Date de publication:
05 Aug 2024
05 Aug 2024
Historique:
revised:
19
07
2024
received:
02
04
2024
accepted:
23
07
2024
medline:
5
8
2024
pubmed:
5
8
2024
entrez:
5
8
2024
Statut:
aheadofprint
Résumé
We describe initial, current, and future aspects of complement activation and inhibition in the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare but severe hematological disorder characterized by complement-mediated intravascular hemolysis resulting in anemia and severe thrombosis. Insights into the complement-mediated pathophysiology ultimately led to regulatory approval of the first-in-class complement inhibitor, eculizumab, in 2007. This anti-complement C5 therapy resulted in the stabilization of many hematologic parameters and dramatically reduced the often fatal, coagulant-resistant thrombotic events. Despite the remarkable clinical success, a substantial proportion of PNH patients experience suboptimal clinical responses during anti-C5 therapy. We describe the identification and mechanistic dissection of four unexpected processes responsible for such suboptimal clinical responses: (1) pharmacokinetic and (2) pharmacodynamic intravascular breakthrough hemolysis, (3) continuing low-level residual intravascular hemolysis, and (4) extravascular hemolysis. Novel complement therapeutics mainly targeting different complement proteins proximal in the cascade attempt to address these remaining problems. With five approved complement inhibitors in the clinic and many more being evaluated in clinical trials, PNH remains one of the complement diseases with the highest intensity of clinical research. Mechanistically unexpected breakthrough events occur not only with C5 inhibitors but also with proximal pathway inhibitors, which require further mechanistic elaboration.
Identifiants
pubmed: 39101294
doi: 10.1002/eji.202350817
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2350817Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : SCHM3018/2-1
Organisme : Deutsche Forschungsgemeinschaft
ID : SCHM3018/2-2
Organisme : Deutsche Forschungsgemeinschaft
ID : SCHM3018/4-1(495891565)
Informations de copyright
© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.
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