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6 results on '"C3 inhibitors"'

1. Pegcetacoplan för behandling av paroxysmal nokturn hemoglobinuri – effektivitet och jämförelse med eculizumab

Author

Pelkonen, Essi and Pelkonen, Essi

Abstract

Introduktion: Paroxysmal nokturn hemoglobinuri (PNH) är en kronisk, förvärvad, mycket sällsynt sjukdom som kännetecknas av komplementmedierad intravaskulär hemolys och är potentiellt livshotande. Sjukdomen börjar med en störning hos en hematopoetisk stamcell vilket leder till att patienter med PNH får röda blodceller som är känsliga för aktiverat komplementsystem och membranattackkomplexet (MAC). PNH kan ge symtom som exempelvis anemi, trombos och trötthet. PNH kan behandlas med komplementhämmare som förhindrar komplementaktivering och därmed komplementmedierad intravaskulär hemolys. Den först utvecklade komplementhämmaren eculizumab är en C5-hämmare som kontrollerar intravaskulär hemolys. Många patienter visar dock tecken på extravaskulär hemolys under behandling med eculizumab. Därför utvecklades det en C3-hämmare pegcetacoplan som ska även blockera extravaskulär hemolys. Syfte: Syftet med detta arbete var att studera pegcetacoplans effektivitet i komplementhämmare-naiva patienter och effektivitet i jämförelse med eculizumab vid behandling av PNH. Syftet var även att analysera skillnader i effektivitet mellan pegcetacoplan och eculizumab vid behandling av PNH. Metod: Detta examensarbete var ett litteraturarbete där sex vetenskapliga artiklar inkluderades baserat på inklusions- och exklusionskriterier. Inklusionskriterier var klinisk studie som analyserade pegcetacoplans effektivitet hos patienter med PNH. Exklusionskriterier var bland annat post hoc-analyser och fallrapporter. Artikelsökning gjordes i databasen PubMed med sökorden ”paroxysmal nocturnal hemoglobinuria pegcetacoplan”. Resultat: Pegcetacoplan-behandling ledde till och/eller bibehöll förbättringar gällande bland annat hemoglobinnivåer och LDH-nivåer hos patienter med PNH i alla sex studier. I PHAROAH och PADDOCK/PALOMINO visades en ökning av klonal distribution av typ II och typ III röda blodceller och minskning av C3 på typ II och typ III celler, vilket tolkades som att pegcetacoplan skyddar dessa ce, Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, acquired, rare disease characterized by complement-mediated intravascular hemolysis and is potentially life-threatening. The disease begins with a disorder of a hematopoietic stem cell, which results in patients with PNH having red blood cells that are sensitive to complement activation and the membrane attack complex (MAC). PNH can cause symptoms such as anemia, thrombosis and fatigue. PNH can be treated with complement inhibitors that prevent complement activation and thereby complement-mediated intravascular hemolysis. The first complement inhibitor developed, eculizumab, is a C5 inhibitor that controls intravascular hemolysis. However, many patients show signs of extravascular hemolysis during treatment with eculizumab. Therefore, a C3 inhibitor pegcetacoplan was developed that should also block extravascular hemolysis. Aim: The aim of this study was to evaluate the efficacy of pegcetacoplan in complement inhibitor-naïve patients and efficacy in comparison with eculizumab in the treatment of PNH. The aim was also to analyze differences in effectiveness between pegcetacoplan and eculizumab in the treatment of PNH. Method: This thesis was a literature review in which six scientific articles were analyzed. Inclusion criteria were clinical trial analyzing the efficacy of pegcetacoplan in patients with PNH. Exclusion criteria included post hoc analyzes and case reports. An article search was made in the PubMed database with the keywords "paroxysmal nocturnal hemoglobinuria pegcetacoplan". Results: Pegcetacoplan treatment led to and/or maintained improvements in, among other things, hemoglobin levels and LDH levels in patients with PNH in all six studies. In the PHAROAH and PADDOCK/PALOMINO studies, an increase in the clonal distribution of type II and type III red blood cells and a decrease in C3 on type II and type III cells were shown, which was interpreted as pegcetacoplan protecting these cells

Published
2024

2. Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery.

Author

Mastellos, Dimitrios C., Reis, Edimara S., Ricklin, Daniel, Smith, Richard J., and Lambris, John D.

Subjects
*INFLAMMATION, *HUMAN genetic variation, *TARGETED drug delivery, *DRUG efficacy, *KIDNEY glomerulus diseases
Abstract

Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk. Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G). Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Published
2017
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3. Design of a modified mouse protein with ligand binding properties of its human analog by molecular dynamics simulations: The case of C3 inhibition by compstatin

Author

Tamamis, Phanourios, Pierou, P., Mytidou, C., Floudas, C. A., Morikis, D., Archontis, Georgios Z., Tamamis, Phanourios [0000-0002-3342-2651], and Archontis, Georgios Z. [0000-0002-7750-8641]

Subjects
Innate immune response, Models, Molecular, Primates, Complement system, ligand binding, Mice, Transgenic, Molecular dynamics, Molecular Dynamics Simulation, Ligands, Crystallography, X-Ray, Peptides, Cyclic, complement component C3, Mice, protein conformation, binding affinity, Compstatin analogs, Humans, Animals, Animalia, Mus musculus, human, protein interaction, Amino Acid Sequence, protein structure, Complement Activation, mouse, nonhuman, Rattus, article, compstatin, Complement C3, peptide, unclassified drug, priority journal, Mammalia, Peptides, C3 inhibitors, Sequence Alignment, Protein Binding
Abstract

The peptide compstatin and its derivatives inhibit the complement-component protein C3 in primate mammals and are potential therapeutic agents against the unregulated activation of complement in humans, but are inactive against C3 from lower mammals. Recent molecular dynamics (MD) simulations showed that the most potent compstatin analog comprised entirely of natural amino acids (W4A9) had a smaller affinity for rat C3, due to reproducible changes in the rat protein structure with respect to the human protein, which eliminated or weakened specific protein-ligand interactions seen in the human C3:W4A9 complex. Here, we study by MD simulations three W4A9 complexes with the mouse C3 protein, and two "transgenic" mouse derivatives, containing a small number (6-9) of human C3 substitutions. The mouse complex experiences the conformational changes and affinity reduction of the rat complex. In the "transgenic" complexes, the conformation remains closer to that of the human complex, the protein-ligand interactions are improved, and the affinity for compstatin becomes "human-like." The present work creates new avenues for a compstatin-sensitive animal model. A similar strategy, involving the comparison of a series of complexes by MD simulations, could be used to design "transgenic" sequences in other systems. © 2011 Wiley-Liss, Inc. 79 11 3166 3179 Cited By :14

Published
2011

4. Species specificity of the complement inhibitor compstatin investigated by all-atom molecular dynamics simulations

Author

Tamamis, Phanourios, Morikis, D., Floudas, C. A., Archontis, Georgios Z., Archontis, Georgios Z. [0000-0002-7750-8641], and Tamamis, Phanourios [0000-0002-3342-2651]

Subjects
Innate immune response, Models, Molecular, Primates, Complement system, X ray diffraction, Protein Conformation, Molecular Sequence Data, Molecular Dynamics Simulation, Peptides, Cyclic, Species Specificity, X-Ray Diffraction, Compstatin analogs, Humans, Animals, human, protein interaction, Amino Acid Sequence, protein structure, Complement Inactivator Proteins, nonhuman, Molecular dynamics simulations, Rattus, fungi, article, complement inhibitor, compstatin, Complement C3, simulation, molecular dynamics, unclassified drug, Rats, priority journal, Mammalia, mutation, C3 inhibitors, Sequence Alignment
Abstract

The development of compounds to regulate the activation of the complement system in non-primate species is of profound interest because it can provide models for human diseases. The peptide compstatin inhibits protein C3 in primate mammals and is a potential therapeutic agent against unregulated activation of complement in humans but is inactive against nonprimate species. Here, we elucidate this species specificity of compstatin by molecular dynamics simulations of complexes between the most potent natural compstatin analog and human or rat C3. The results are compared against an experimental conformation of the human complex, determined recently by X-ray diffraction at 2.4-å resolution. The human complex simulations provide information on the relative contributions to stability of specific C3 and compstatin residues. In the rat simulations, the protein undergoes reproducible conformational changes, which eliminate or weaken specific interactions and reduce the complex stability. The simulation insights can be used to design improved compstatin-based inhibitors for human C3 and active inhibitors against lower mammals. © 2010 Wiley-Liss, Inc. 78 12 2655 2667 Cited By :19

Published
2010

5. Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria.

Author

Mastellos DC, Reis ES, Yancopoulou D, Risitano AM, and Lambris JD

Subjects
Hemoglobinuria, Paroxysmal pathology, Hemolysis, Humans, Complement Inactivating Agents therapeutic use, Complement System Proteins physiology, Hemoglobinuria, Paroxysmal therapy
Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is widely regarded as an archetypal complement-mediated disorder that has propelled complement drug discovery in recent decades. Its pathology is driven by chronic complement dysregulation resulting from the lack of the glycosyl phosphatidyl inositol-linked regulators DAF and CD59 on susceptible erythrocytes. This complement imbalance fuels persistent C3 activation on affected erythrocytes, which culminates in chronic complement-mediated intravascular hemolysis. The clinical application of eculizumab, a humanized anti-C5 antibody that blocks terminal pathway activation, has led to drastic improvement of therapeutic outcomes but has also unveiled hitherto elusive pathogenic mechanisms that are now known to contribute to the clinical burden of a significant proportion of patients with PNH. These emerging clinical needs have sparked a true resurgence of complement therapeutics that offer the promise of even more effective, disease-tailored therapies for PNH. Here, we review the current state of complement therapeutics with a focus on the clinical development of C3-targeted and alternative pathway-directed drug candidates for the treatment of PNH. We also discuss the relative advantages and benefits offered by each complement-targeting approach, including translational considerations that might leverage a more comprehensive clinical intervention for PNH., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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6. Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape.

Author

Mastellos DC, Ricklin D, Yancopoulou D, Risitano A, and Lambris JD

Subjects
Antibodies, Monoclonal, Humanized therapeutic use, Complement C3 antagonists & inhibitors, Complement C3 metabolism, Complement C5 antagonists & inhibitors, Complement C5 metabolism, Erythrocytes metabolism, Hemoglobinuria, Paroxysmal pathology, Hemolysis, Humans, Peptides therapeutic use, Complement System Proteins metabolism, Hemoglobinuria, Paroxysmal therapy
Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder associated with an acquired deficiency in glycophosphatidylinositol-anchor biosynthesis that renders erythrocytes susceptible to complement attack. Intravascular hemolysis via the membrane attack complex is a clinical hallmark of the disease, and C5 blockade is currently the only approved treatment for PNH. However, residual anemia is an emerging observation for many PNH patients receiving anti-C5 treatment. A range of complement-targeted therapeutic approaches, encompassing surface-directed inhibition of C3 convertases, blockade of membrane attack complex assembly or C3 interception using peptidic inhibitors, has yielded promising results and offers leverage for even more effective treatment of PNH. This article discusses recent advances in this rapidly evolving field, integrating critical perspectives from preclinical PNH models and diverse complement modulation strategies with genetic insights and therapy response profiles. It also evaluates the relative efficacy, limitations and benefits afforded by C3 or C5 inhibition in the context of PNH therapeutics.

Published
2014
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