RESUMEN
The complement cascade is a vital system in the human body's defense against pathogens. During the natural aging process, it has been observed that this system is imperative for ensuring the integrity and homeostasis of the retina. While this system is critical for proper host defense and retinal integrity, it has also been found that dysregulation of this system may lead to certain retinal pathologies, including geographic atrophy and diabetic retinopathy. Targeting components of the complement system for retinal diseases has been an area of interest, and in vivo, ex vivo, and clinical trials have been conducted in this area. Following clinical trials, medications targeting the complement system for retinal disease have also become available. In this manuscript, we discuss the pathophysiology of complement dysfunction in the retina and specific pathologies. We then describe the results of cellular, animal, and clinical studies targeting the complement system for retinal diseases. We then provide an overview of complement inhibitors that have been approved by the Food and Drug Administration (FDA) for geographic atrophy. The complement system in retinal diseases continues to serve as an emerging therapeutic target, and further research in this field will provide additional insights into the mechanisms and considerations for treatment of retinal pathologies.
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Proteínas del Sistema Complemento , Enfermedades de la Retina , Humanos , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/fisiopatología , Enfermedades de la Retina/inmunología , Proteínas del Sistema Complemento/fisiología , Animales , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/fisiopatología , Retina/efectos de los fármacos , Retina/inmunologíaRESUMEN
The complement system plays a critical role in the innate immune response, acting as a first line of defense against invading pathogens. However, dysregulation of the complement system is implicated in the pathogenesis of numerous diseases, ranging from Alzheimer's to age-related macular degeneration and rare blood disorders. As such, complement inhibitors have enormous potential to alleviate disease burden. While a few complement inhibitors are in clinical use, there is still a significant unmet medical need for the discovery and development of novel inhibitors to treat patients suffering from disorders of the complement system. A key hurdle in the development of complement inhibitors has been the determination of their mechanism of action. Progression along the complement cascade involves the formation of numerous multimeric protein complexes, creating the potential for inhibitors to act at multiple nodes in the pathway. This is especially true for molecules that target the central component C3 and its fragment C3b, which serve a dual role as a substrate for the C3 convertases and as a scaffolding protein in both the C3 and C5 convertases. Here, we report a step-by-step in vitro reconstitution of the complement alternative pathway using bio-layer interferometry. By physically uncoupling each step in the pathway, we were able to determine the kinetic signature of inhibitors that act at single steps in the pathway and delineate the full mechanism of action of known and novel C3 inhibitors. The method could have utility in drug discovery and further elucidating the biochemistry of the complement system.
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Vía Alternativa del Complemento , Humanos , Vía Alternativa del Complemento/efectos de los fármacos , Complemento C3/metabolismo , Complemento C3/antagonistas & inhibidores , Inactivadores del Complemento/farmacología , Complemento C3b/metabolismoRESUMEN
ABSTRACT: Excessively activated or dysregulated complement activation may contribute to the pathogenesis of a wide range of human diseases, thus leading to a surge in complement inhibitors. Herein, we developed a human-derived and antibody-like C3b-targeted fusion protein (CRIg-FH-Fc) x2, termed CG001, that could potently block all 3 complement pathways. Complement receptor of the immunoglobulin superfamily (CRIg) and factor H (FH) bind to distinct sites in C3b and synergistically inhibit complement activation. CRIg occupancy in C3b prevents the recruitment of C3 and C5 substrates, whereas FH occupancy in C3b accelerates the decay of C3/C5 convertases and promotes the factor I-mediated degradation and inactivation of C3b. CG001 also showed therapeutic effects in alternative pathways-induced hemolytic mouse and classical pathways-induced mesangial proliferative glomerulonephritis rat models. In the pharmacological/toxicological evaluation in rats and cynomolgus monkeys, CG001 displayed an antibody-like pharmacokinetic profile, a convincing complement inhibitory effect, and no observable toxic effects. Therefore, CG001 holds substantial potential for human clinical studies.
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Complemento C3b , Animales , Humanos , Ratas , Ratones , Complemento C3b/metabolismo , Inactivadores del Complemento/farmacología , Inactivadores del Complemento/uso terapéutico , Macaca fascicularis , Activación de Complemento/efectos de los fármacos , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Factor H de Complemento/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de MedicamentosRESUMEN
The approval of complement inhibitory therapeutic agents for the treatment of geographic atrophy (GA) has highlighted the need for reliable and reproducible measurement of disease progression and therapeutic efficacy. Due to its availability and imaging characteristics optical coherence tomography (OCT) is the method of choice. Using OCT analysis based on artificial intelligence (AI), the therapeutic efficacy of pegcetacoplan was demonstrated at the levels of both the retinal pigment epithelium (RPE) and photoreceptors (PR). Cloud-based solutions that enable monitoring of GA are already available.
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Biomarcadores , Inactivadores del Complemento , Atrofia Geográfica , Tomografía de Coherencia Óptica , Humanos , Atrofia Geográfica/tratamiento farmacológico , Atrofia Geográfica/metabolismo , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Resultado del Tratamiento , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/diagnóstico por imagen , Epitelio Pigmentado de la Retina/metabolismoRESUMEN
BACKGROUND: This study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG). METHODS: Adolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded. RESULTS: Eleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were -5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and -2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. CONCLUSIONS: Eculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.
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Anticuerpos Monoclonales Humanizados , Inactivadores del Complemento , Miastenia Gravis , Humanos , Adolescente , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Miastenia Gravis/tratamiento farmacológico , Masculino , Femenino , Niño , Inactivadores del Complemento/administración & dosificación , Inactivadores del Complemento/farmacología , Resultado del Tratamiento , Calidad de Vida , Evaluación de Resultado en la Atención de SaludRESUMEN
Crovalimab (®; PiaSky) is a humanized, anti-complement component C5 (anti-C5) recycling monoclonal antibody developed by Chugai Pharmaceutical, in collaboration with Roche, which is being investigated for the treatment of complement-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, lupus nephritis and sickle cell disease. Crovalimab targets C5, inhibiting its cleavage to C5a and C5b, thus blocking the terminal complement pathway and preventing intravascular haemolysis in PNH. Crovalimab is designed to bind to the antigen repeatedly, resulting in sustained complement inhibition at a lower dosage, and allowing for once-monthly subcutaneous administration. In February 2024, subcutaneous crovalimab received its first approval in China for the treatment of adolescents and adults (aged ≥ 12 years) with PNH who have not been previously treated with complement inhibitors. Crovalimab has since been approved in Japan in March for use in the treatment of PNH, including in treatment-naïve and previously treated patients. Crovalimab is also under regulatory review for the treatment of naïve and previously treated patients with PNH in multiple countries, including the USA and the European Union. This article summarizes the milestones in the development of crovalimab leading to this first approval in China for the treatment of PNH.
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Anticuerpos Monoclonales Humanizados , Aprobación de Drogas , Hemoglobinuria Paroxística , Humanos , Hemoglobinuria Paroxística/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/efectos adversos , Complemento C5/antagonistas & inhibidores , China , Adulto , Adolescente , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológicoRESUMEN
OBJECTIVE: Eculizumab and ravulizumab are complement protein C5 inhibitors, showing efficacy and tolerability for patients with anti-acetylcholine receptor-positive (AChR+) generalized myasthenia gravis (gMG) in phase 3 clinical trials and subsequent analyses. The purpose of the present study was to evaluate the clinical significance of eculizumab and switching to ravulizumab for refractory AChR+ gMG patients in the real-world experience. METHODS: Among the database of Japan MG registry survey 2021, we studied AChR+ gMG patients who received eculizumab. We also evaluated these patients who switched from eculizumab to ravulizumab. Responder was defined as an improvement of at least 3 points in MG-ADL. We performed a questionnaire of preference between eculizumab and ravulizumab. RESULTS: Among 1,106 patients with AChR+ gMG, 36 patients (3%) received eculizumab (female 78%, mean age 56.0 years). Eculizumab was preferentially used in severe and refractory MG patients. The duration of eculizumab treatment was 35 months on average. MG-ADL improved from 9.4 ± 4.9 to 5.9 ± 5.1, and 25 (70%) of the 36 gMG patients were responders. Postintervention status was markedly improved after the eculizumab treatment. Of 13 patients who did not continue eculizumab, 6 showed insufficiencies. Early onset MG was most effective. However, 15 patients switching from eculizumab to ravulizumab kept favorable response and tolerability. Questionnaire surveys showed preference for ravulizumab over eculizumab. INTERPRETATION: Eculizumab and switching to ravulizumab showed to be effective for refractory AChR+ gMG patients in clinical settings.
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Anticuerpos Monoclonales Humanizados , Inactivadores del Complemento , Miastenia Gravis , Humanos , Miastenia Gravis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Adulto , Inactivadores del Complemento/administración & dosificación , Inactivadores del Complemento/farmacología , Sustitución de Medicamentos , Sistema de Registros , JapónRESUMEN
Disorder of complement response is a significant pathogenic factor causing some autoimmune and inflammation diseases. The Ornithodoros moubata Complement Inhibitor (OmCI), a small 17 kDa natural protein, was initially extracted from soft tick salivary glands. The protein was found binding to complement C5 specifically, inhibiting the activation of the complement pathway, which is a successful therapeutic basis of complement-mediated diseases. However, a short half-life due to rapid renal clearance is a common limitation of small proteins for clinical application. In this study, we extended the half-life of OmCI by modifying it with fatty acid, which was a method used to improve the pharmacokinetics of native peptides and proteins. Five OmCI mutants were initially designed, and single-site cysteine mutation was introduced to each of them. After purification, four OmCI mutants were obtained that showed similar in vitro biological activities. Three mutants of them were subsequently coupled with different fatty acids by nucleophilic substitution. In total, 15 modified derivatives were screened and tested for anticomplement activity in vitro. The results showed that coupling with fatty acid would not significantly affect their complement-inhibitory activity (CH50 and AH50). OmCIT90C-CM02 and OmCIT90C-CM05 were validated as the applicable OmCI bioconjugates for further pharmacokinetic assessments, and both showed improved plasma half-life in mice compared with unmodified OmCI (15.86, 17.96 vs 2.57 h). In summary, our data demonstrated that OmCI conjugated with fatty acid could be developed as the potential long-acting C5 complement inhibitor in the clinic.
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Complemento C5 , Ácidos Grasos , Ornithodoros , Animales , Ácidos Grasos/química , Ratones , Complemento C5/antagonistas & inhibidores , Diseño de Fármacos , Semivida , Proteínas Inactivadoras de Complemento/farmacología , Proteínas Inactivadoras de Complemento/química , Inactivadores del Complemento/farmacología , Inactivadores del Complemento/farmacocinética , Inactivadores del Complemento/química , HumanosRESUMEN
INTRODUCTION: Myasthenia gravis (MG) is an autoimmune condition targeting the neuromuscular junction, which manifests with neuromuscular symptoms of varying severity and significant morbidity. The mainstay of treatment in MG is mitigation of the immune cascade with steroids and non-steroidal immunosuppressive therapies. The therapeutic strategies in MG are transitioning from broad and indiscriminate immunosuppression to novel agents targeting key steps in MG pathogenesis, including T cell activation, B cell proliferation, complement activation, maintenance of pathogenic antibody production, and proinflammatory cytokine production. AREAS COVERED: In this review, an overview of the pathogenesis of MG and traditional MG therapies is presented, followed by a discussion of the novel MG drugs that have been evaluated in phase 3 clinical trials with an emphasis on those which have received regulatory approval. EXPERT OPINION: Novel MG therapeutics belonging to the classes of complement inhibitors, neonatal Fc receptor (FcRn) inhibitors and B cell depletors, as well as the other emerging MG drugs in the pipeline constitute promising treatment strategies with potentially better efficacy and safety compared to the conventional MG treatments. However, further long-term research is needed in order to optimize the implementation of these new treatment options for the appropriate patient populations.
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Inmunosupresores , Miastenia Gravis , Humanos , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/inmunología , Miastenia Gravis/terapia , Inmunosupresores/uso terapéutico , Animales , Linfocitos B/inmunología , Linfocitos B/efectos de los fármacos , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacologíaRESUMEN
The complement is an important arm of the innate immune system, once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammation. Recent studies have shown that over-activated complement is the main proinflammatory system of autoimmune diseases (ADs). In addition, activated complements interact with autoantibodies, immune cells exacerbate inflammation, further worsening ADs. With the increasing threat of ADs to human health, complement-based immunotherapy has attracted wide attention. Nevertheless, efficient and targeted delivery of complement inhibitors remains a significant challenge owing to their inherent poor targeting, degradability, and low bioavailability. Nanosystems offer innovative solutions to surmount these obstacles and amplify the potency of complement inhibitors. This prime aim to present the current knowledge of complement in ADs, analyse the function of complement in the pathogenesis and treatment of ADs, we underscore the current situation of nanosystems assisting complement inhibitors in the treatment of ADs. Considering technological, physiological, and clinical validation challenges, we critically appraise the challenges for successfully translating the findings of preclinical studies of these nanosystem assisted-complement inhibitors into the clinic, and future perspectives were also summarised. (The graphical abstract is by BioRender.).
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Enfermedades Autoinmunes , Inactivadores del Complemento , Proteínas del Sistema Complemento , Humanos , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Inactivadores del Complemento/administración & dosificación , Inactivadores del Complemento/farmacología , Animales , Proteínas del Sistema Complemento/inmunología , Nanopartículas , Activación de Complemento/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Inmunoterapia/métodosRESUMEN
The Complement System is an evolutionarily conserved component of immunity that plays a key role in host defense against infections and tissue homeostasis. However, the dysfunction of the Complement System can result in tissue damage and inflammation, thereby contributing to the development and progression of various renal diseases, ranging from atypical Hemolytic Uremic Syndrome to glomerulonephritis. Therapeutic interventions targeting the complement system have demonstrated promising results in both preclinical and clinical studies. Currently, several complement inhibitors are being developed for the treatment of complement-mediated renal diseases. This review aims to summarize the most recent insights into complement activation and therapeutic inhibition in renal diseases. Furthermore, it offers potential directions for the future rational use of complement inhibitor drugs in the context of renal diseases.
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Activación de Complemento , Inactivadores del Complemento , Proteínas del Sistema Complemento , Progresión de la Enfermedad , Enfermedades Renales , Humanos , Proteínas del Sistema Complemento/inmunología , Enfermedades Renales/inmunología , Enfermedades Renales/etiología , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Animales , Síndrome Hemolítico Urémico Atípico/inmunología , Glomerulonefritis/inmunologíaRESUMEN
Danicopan (Voydeya®) is an oral complement factor D inhibitor that is being developed by Alexion AstraZeneca Rare Disease as add-on treatment to ravulizumab or eculizumab for patients with clinically significant extravascular haemolysis. Danicopan recently received approval in Japan for the treatment of adults with paroxysmal nocturnal haemoglobinuria (PNH) when used in addition to a complement component 5 (C5) inhibitor. Subsequently, the European Medicines Agency adopted a positive opinion recommending the granting of marketing authorisation for danicopan for the treatment of patients with PNH who continue to have residual haemolytic anaemia despite treatment with a complement C5 inhibitor. This article summarizes the milestones in the development of danicopan leading to this first approval for PNH.
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Anticuerpos Monoclonales Humanizados , Aprobación de Drogas , Hemoglobinuria Paroxística , Humanos , Hemoglobinuria Paroxística/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/efectos adversos , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacologíaRESUMEN
Iptacopan (FABHALTA®) is an oral complement Factor B inhibitor developed by Novartis Pharmaceuticals for the treatment of complement-mediated diseases. Acting upstream of complement 5 in the alternative pathway, iptacopan inhibits both terminal complement-mediated intravascular haemolysis and complement 3-mediated extravascular haemolysis. On 5 December 2023, iptacopan received approval in the USA for the treatment of adults with paroxysmal nocturnal haemoglobinuria (PNH). This article summarizes the milestones in the development of iptacopan leading to this first approval for PNH.
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Aprobación de Drogas , Hemoglobinuria Paroxística , Humanos , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Hemoglobinuria Paroxística/tratamiento farmacológico , Hemólisis/efectos de los fármacos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
The introduction of a therapeutic anti-C5 antibody into clinical practice in 2007 inspired a surge into the development of complement-targeted therapies. This has led to the recent approval of a C3 inhibitory peptide, an antibody directed against C1s and a full pipeline of several complement inhibitors in preclinical and clinical development. However, no inhibitor is available that efficiently inhibits all three complement initiation pathways and targets host cell surface markers as well as complement opsonins. To overcome this, we engineered a novel fusion protein combining selected domains of the three natural complement regulatory proteins decay accelerating factor, factor H and complement receptor 1. Such a triple fusion complement inhibitor (TriFu) was recombinantly expressed and purified alongside multiple variants and its building blocks. We analyzed these proteins for ligand binding affinity and decay acceleration activity by surface plasmon resonance. Additionally, we tested complement inhibition in several in vitro/ex vivo assays using standard classical and alternative pathway restricted hemolysis assays next to hemolysis assays with paroxysmal nocturnal hemoglobinuria erythrocytes. A novel in vitro model of the alternative pathway disease C3 glomerulopathy was established to evaluate the potential of the inhibitors to stop C3 deposition on endothelial cells. Next to the novel engineered triple fusion variants which inactivate complement convertases in an enzyme-like fashion, stoichiometric complement inhibitors targeting C3, C5, factor B, and factor D were tested as comparators. The triple fusion approach yielded a potent complement inhibitor that efficiently inhibits all three complement initiation pathways while targeting to surface markers.
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Factor H de Complemento , Receptores de Complemento 3b , Proteínas Recombinantes de Fusión , Humanos , Factor H de Complemento/metabolismo , Factor H de Complemento/genética , Factor H de Complemento/química , Factor H de Complemento/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/farmacología , Activación de Complemento/efectos de los fármacos , Antígenos CD55/genética , Antígenos CD55/metabolismo , Hemólisis/efectos de los fármacos , Vía Alternativa del Complemento/efectos de los fármacos , Inactivadores del Complemento/farmacología , Eritrocitos/metabolismoAsunto(s)
Anticuerpos Monoclonales Humanizados , Miastenia Gravis , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Miastenia Gravis/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Historically, the complement system (classical, lectin, alternative, and terminal pathways) is known to play a crucial role in the etiopathogenesis of many kidney diseases. Direct or indirect activation in these settings is revealed by consumption of complement proteins at the serum level and kidney tissue deposition seen by immunofluorescence and electron microscopy. The advent of eculizumab has shown that complement inhibitors may improve the natural history of certain kidney diseases. Since then, the number of available therapeutic molecules and experimental studies on complement inhibition has increased exponentially. In our narrative review, we give a summary of the main complement inhibitors that have completed phase II and phase III studies or are currently used in adult and pediatric nephrology. The relevant full-text works, abstracts, and ongoing trials (clinicaltrials.gov site) are discussed. Data and key clinical features are reported for eculizumab, ravulizumab, crovalimab, avacopan, danicopan, iptacopan, pegcetacoplan, and narsoplimab. Many of these molecules have been shown to be effective in reducing proteinuria and stabilizing kidney function in different complement-mediated kidney diseases. Thanks to their efficacy and target specificity, these novel drugs may radically improve the outcome of complement-mediated kidney diseases, contributing to an improvement in our understanding of their underlying pathophysiology.
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Síndrome Hemolítico Urémico Atípico , Glomerulonefritis Membranoproliferativa , Enfermedades Renales , Adulto , Niño , Humanos , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Complemento C3/metabolismo , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Activación de ComplementoRESUMEN
The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated complement activity is associated with unwanted or non-resolving immune responses and inflammation, which induce or exacerbate the pathogenesis of a broad range of inflammatory and autoimmune diseases. Although the merit of targeting complement clinically has long been acknowledged, the overall complement drug approval rate has been modest. However, the success of the humanised anti-C5 antibody eculizumab in effectively treating paroxysmal nocturnal haemoglobinuria and atypical haemolytic syndrome has revitalised efforts to target complement therapeutically. Increased understanding of complement biology has led to the identification of novel targets for drug development that, in combination with advances in drug discovery and development technologies, has resulted in a surge of interest in bringing new complement therapeutics into clinical use. The rising number of approved drugs still almost exclusively target rare diseases, but the substantial pipeline of up-and-coming treatment options will possibly provide opportunities to also expand the clinical targeting of complement to common diseases.
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Enfermedades Autoinmunes , Hemoglobinuria Paroxística , Humanos , Inactivadores del Complemento/farmacología , Inactivadores del Complemento/uso terapéutico , Proteínas del Sistema Complemento/fisiología , Hemoglobinuria Paroxística/tratamiento farmacológico , Descubrimiento de DrogasRESUMEN
The dysregulation of complement system activation usually results in acute or chronic inflammation and can contribute to the development of various diseases. Although the activation of complement pathways is essential for innate defense, exacerbated activity of this system may be harmful to the host. Thus, drugs with the potential to inhibit the activation of the complement system may be important tools in therapy for diseases associated with complement system activation. The synthetic peptides Cp40 and PMX205 can be highlighted in this regard, given that they selectively inhibit the C3 and block the C5a receptor (C5aR1), respectively. The zebrafish (Danio rerio) is a robust model for studying the complement system. The aim of the present study was to use in silico computational modeling to investigate the hypothesis that these complement system inhibitor peptides interact with their target molecules in zebrafish, for subsequent in vivo validation. For this, we analyzed molecular docking interactions between peptides and target molecules. Our study demonstrated that Cp40 and the cyclic peptide PMX205 have positive interactions with their respective zebrafish targets, thus suggesting that zebrafish can be used as an animal model for therapeutic studies on these inhibitors.
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Activación de Complemento , Pez Cebra , Animales , Simulación del Acoplamiento Molecular , Simulación por Computador , Inactivadores del Complemento/farmacologíaRESUMEN
Two central questions in COVID-19 treatment which should be considered are: "How does the imbalance of the complement system affect the therapeutic approaches?" and "Do we consider complement inhibitors in therapeutic protocols?". The complement system is a double-edged sword since it may either promote immune responses against COVID-19 or contribute to destructive inflammation in the host. Therefore, it is crucial to regulate this system with complement inhibitors. In this manuscript, we discuss the molecular mechanisms of complement and complement inhibitors in COVID-19 patients. We searched the terms "COVID-19", "Complement", "Complement inhibitor", "SARS-CoV-2", and all complement fragments and inhibitors from 2000 to 2022 in PubMed and google scholar and checked the pathways in "KEGG pathway database". Complement is not well-appreciated in the treatment protocols despite its multiple roles in the disease, and most of the preventive anti-inflammatory therapeutic approaches did not include a complement inhibitor in COVID-19 therapeutic protocols. In this review article, we discussed the most recent studies regarding complement components mediated interventions and the mechanism of these interventions in COVID-19 patients. Since the control of the complement system overactivation is associated with a better prognosis in the initial stages of COVID-19, heparin, anti-thrombin, C1-inhibitor, montelukast, and hydralazine can be effective in the initial stages of this viral infection. Recombinant complement activation (RCA) proteins are more effective in regulating complement compared to terminal pathway therapeutic approaches such as the C3a and C5a inhibitors.
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COVID-19 , Humanos , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Activación de Complemento , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Factores InmunológicosRESUMEN
A refined understanding of the role of complement in the pathogenesis of glomerular and other kidney diseases has, over the past two decades, been matched by the development of novel, complement-targeting therapies. As we increasingly recognize the important role that complement activation across all three pathways-classical, lectin and alternative-plays in glomerular lesions both rare (e.g. C3 glomerulopathy) and common (e.g. immunoglobulin A nephropathy), we can identify avenues for precise, targeted approaches to modifying the natural history of these kidney diseases. In this review, we survey the evidence on using complement inhibition from the earliest, small-scale studies focusing on C5-targeting agents to more recent, large, multicenter, randomized trials utilizing complement blockade higher up in the complement pathway at the level of C3. We conclude by examining where the field of complement targeting therapy may be headed in light of these studies.