ArticleBlood2017
Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation.
Article in Blood, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
83 citing papers in PubMed, 138 citations in OpenAlex.
- Hemolysis events in the phase 3 PEGASUS study of pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria.Blood advances · 2024Trial
- Phase II trials of zilucoplan in paroxysmal nocturnal hemoglobinuria.Haematologica · 2024Trial
- One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab.European journal of haematology · 2021Trial
- Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies.British journal of haematology · 2020Trial
- Mapping of C5-Blocking Monoclonal Antibodies Reveals New C5 Inhibitory Epitopes and Novel Modes of C5 Inhibition.Immunology · 2026Article
- In vivo evidence of effective complement modulation by TriFu in comparison to C5 inhibition and complement depletion.Blood advances · 2026Article
- Inhibition of Classical and Alternative Complement Pathway by Ravulizumab and Eculizumab.Annals of clinical and translational neurology · 2026Article
- Design of miniprotein inhibitors targeting complement C9 to block membrane attack complex assembly.Nature communications · 2026Article
- Evaluating Drug-Target Complexes in Therapeutic Monoclonal Antibodies Using A4F-MALS: Implications for Drug Development and Clinical Design.Journal of immunology research · 2026Article
- Beyond Terminal Blockade: A Mechanism-Based Approach to Complement Inhibitor Selection in Paroxysmal Nocturnal Hemoglobinuria.Drug design, development and therapy · 2026Review
- The Pleiotropic Effect of Complement C5a-C5aR1 Pathway in Diseases: From Immune Regulation to Targeted Therapy.International journal of molecular sciences · 2025Review
- Insights in bone marrow failure syndromes: take home messages from the 3rd ESH-EBMT-EHA-IPIG translational research conference.Bone marrow transplantation · 2025Article
- Action of the Terminal Complement Pathway on Cell Membranes.The Journal of membrane biology · 2025Review
- The Advancing Landscape of Paroxysmal Nocturnal Hemoglobinuria TreatmentTurkish journal of haematology : official journal of Turkish Society of Haematology · 2025Review
- Review
- A novel and rapid method to purify the human complement opsonin C3b from human plasma.Frontiers in immunology · 2025Article
- C3 mutations and poor pegcetacoplan response in paroxysmal nocturnal hemoglobinuria.Frontiers in immunology · 2025Article
- Paroxysmal Nocturnal Hemoglobinuria, Pathophysiology, Diagnostics, and Treatment.Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie · 2024Review
- Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors.International journal of molecular sciences · 2024Review
- CG001, a C3b-targeted complement inhibitor, blocks 3 complement pathways: development and preclinical evaluation.Blood advances · 2024Article
23 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5, indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin, we determined conditions ex vivo in which C5 inhibition is incomplete. The degree of such residual lytic activity depended on the strength of the complement activator and the resulting surface density of the complement activation product C3b, which autoamplifies via the alternative pathway (AP) amplification loop. We show that at high C3b densities required for binding and activation of C5, both inhibitors reduce but do not abolish this interaction. The decrease of C5 binding to C3b clusters in the presence of C5 inhibitors correlated with the levels of residual hemolysis. However, by employing different C5 inhibitors simultaneously, residual hemolytic activity could be abolished. The importance of AP-produced C3b clusters for C5 activation in the presence of eculizumab was corroborated by the finding that residual hemolysis after forceful activation of the classical pathway could be reduced by blocking the AP. By providing insights into C5 activation and inhibition, our study delivers the rationale for the clinically observed phenomenon of residual terminal pathway activity under eculizumab treatment with important implications for anti-C5 therapy in general.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.