Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surfa...

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Veröffentlicht in:International journal of molecular sciences Jg. 25; H. 17; S. 9477
Hauptverfasser: Hillmen, Peter, Horneff, Regina, Yeh, Michael, Kolev, Martin, Deschatelets, Pascal
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland MDPI AG 01.09.2024
Schlagworte:
Anemia
Antibodies, Monoclonal, Humanized - pharmacology
Antibodies, Monoclonal, Humanized - therapeutic use
Blood
Bone marrow
CD55 Antigens - genetics
CD55 Antigens - metabolism
CD59 Antigens - genetics
CD59 Antigens - metabolism
Cloning
Complement Activation - drug effects
Complement Inactivating Agents - therapeutic use
Disease
FDA approval
Hemoglobinuria, Paroxysmal - drug therapy
Hemoglobinuria, Paroxysmal - metabolism
Humans
Immune system
Laboratories
Leukocytes
Monoclonal antibodies
Mortality
Pathogens
Proteins
Stem cells
Thrombosis
C3 inhibitor
paroxysmal nocturnal hemoglobinuria
factor B inhibitor
factor D inhibitor
complement
pegcetacoplan
C5 inhibitor
ISSN:1422-0067, 1661-6596, 1422-0067
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Zusammenfassung:Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surface proteins, including the complement regulatory proteins CD55 and CD59. With decreased or a lack of CD55 and CD59 expression on their membranes, PNH red blood cells become susceptible to complement-mediated hemolysis (symptoms of which include anemia, dysphagia, abdominal pain, and fatigue), leading to thrombosis. State-of-the-art PNH treatments act by inhibiting the dysregulated complement at distinct points in the activation pathway: late at the C5 level (C5 inhibitors, eculizumab, ravulizumab, and crovalimab), centrally at the C3 level (C3/C3b inhibitors and pegcetacoplan), and early at the initiation and amplification of the alternative pathway (factor B inhibitor, iptacopan; factor D inhibitor, danicopan). Through their differing mechanisms of action, these treatments elicit varying profiles of disease control and offer valuable insights into the molecular underpinnings of PNH. This narrative review provides an overview of the mechanisms of action of the six complement inhibitors currently approved for PNH, with a focus on the C3/C3b-targeted therapy, pegcetacoplan.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25179477