RESUMO
BACKGROUND: No reports have shown histological changes before and after anti-C5 monoclonal antibody treatment in patients with atypical hemolytic uremic syndrome (aHUS). Here, we report a rare case of complement-mediated aHUS with a complement factor H (CFH) mutation and anti-CFH antibodies who underwent multiple kidney biopsies. CASE PRESENTATION: A 53-year-old woman developed aHUS with CFH gene mutation [c.3572C > T (p. Ser1191 Leu)] and anti-CFH antibodies. Her father had succumbed to acute kidney injury (AKI) in his 30 s. She exhibited AKI, thrombocytopenia, and hemolytic anemia with schistocytes. After improving the platelet count with one session of plasma exchange, a kidney biopsy was performed one month after the onset of symptoms. Blood vessel thrombosis, obvious endothelial swelling, endocapillary hypercellularity, and subendothelial exudative lesions in the glomeruli and arterioles were detected. Anti-C5 monoclonal antibody treatment with eculizumab immediately improved disease activity. A second biopsy 3 months later revealed marked improvement of endothelial injuries with residual membrane double contours and exudative lesions. A third biopsy at 17 months after gradual improvement of kidney function showed a further decrease of double contours along with alterations of the exudative lesions to fibrous intimal thickening. CONCLUSIONS: This is the first report showing the pathophysiology of aHUS in the kidneys and the efficacy of anti-C5 monoclonal antibody treatment by presenting serial kidney pathological features before and after anti-C5 monoclonal antibody treatment. Since her CFH mutation was considered the most important pathological condition, treatment centered on eculizumab was administered, resulting in a good long-term prognosis. In addition, kidney pathological resolution in aHUS occurred over 1 year after anti-C5 monoclonal antibody treatment.
Assuntos
Anticorpos Monoclonais Humanizados , Síndrome Hemolítico-Urêmica Atípica , Fator H do Complemento , Humanos , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C5/antagonistas & inibidores , Rim/patologiaRESUMO
Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.
Assuntos
Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/efeitos adversos , Hemólise/efeitos dos fármacos , Complemento C5/antagonistas & inibidores , IdosoRESUMO
Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.
Assuntos
Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/efeitos adversos , Inativadores do Complemento/administração & dosagem , Idoso , Complemento C5/antagonistas & inibidores , Resultado do TratamentoRESUMO
Kidney transplant (KT) candidates with donor-specific antibodies (DSA) exhibit exceedingly high antibody-mediated rejection (ABMR) and allograft loss rates. Currently, treatment of ABMR remains an unmet clinical need. We report the use of the anti-C5 eculizumab and the type-2 anti-CD20 obinutuzumab in two patients with early ABMR. Eculizumab (900 mg IV) led to complete inhibition of the terminal complement cascade (unremarkable AP50 and CH50 activity) and prompt stoppage of complement-dependent antibody-mediated allograft injury (clearance of intra-graft C4d and C5b-9 deposition). Despite complement inhibition, obinutuzumab (1000 mg IV) determined full and long-lasting peripheral B-cell depletion, with significant reduction in all DSA. Graft function improved, remaining stable up to three years of follow-up. No signs of active ABMR and rebound DSA were detected. Obinutuzumab B-cell depletion and inhibition of DSA production were not affected by complement blockage. Further studies are needed to confirm the potential benefit of obinutuzumab in association with complement inhibitors.
Assuntos
Anticorpos Monoclonais Humanizados , Rejeição de Enxerto , Transplante de Rim , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Masculino , Pessoa de Meia-Idade , Complemento C5/antagonistas & inibidores , Complemento C5/imunologia , Feminino , Antígenos CD20/imunologia , Adulto , Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Isoanticorpos/imunologiaRESUMO
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.
Assuntos
Anticorpos Monoclonais Humanizados , Aprovação de Drogas , Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Complemento C5/antagonistas & inibidores , China , Adulto , Adolescente , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/farmacologia , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológicoRESUMO
The complement is a crucial factor of the innate immune system. However, its activation can lead to various diseases, so it needs to be controlled. In mammals, surface-bound complement regulatory proteins safeguard cells from uncontrolled complement-mediated lysis. One of the human complement regulators is CD55, also known as the decay-accelerating factor (DAF), a single-chain, type I cell surface protein anchored to glycosylphosphatidylinositol (GPI). The genetic loss of the complement regulatory protein CD55 leads to a fatal illness known as CHAPLE disease. The complement and innate immunity become hyperactive in this disease, causing angiopathic thrombosis and protein-losing enteropathy. Patients with CHAPLE disease experience abdominal pain, nausea, vomiting, diarrhea, loss of appetite, weight loss, impaired growth, and swelling. This genetic condition has no known cure, and managing its symptoms can be challenging. Pozelimab, a human monoclonal immunoglobulin IgG4 antibody, is a drug that targets the terminal complement protein C5. The drug has a high affinity for both wild-type and variant human C5. Pozelimab has received designations such as fast track, orphan drug, and rare pediatric disease, making it a significant medical breakthrough. It is currently the only available treatment for this disease. In this review, we have summarized the preclinical and clinical data on pozelimab.
Assuntos
Anticorpos Monoclonais Humanizados , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos CD55/metabolismo , Animais , Complemento C5/antagonistas & inibidores , Enteropatias Perdedoras de Proteínas/tratamento farmacológicoRESUMO
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.
Assuntos
Complemento C5 , Ácidos Graxos , Ornithodoros , Animais , Ácidos Graxos/química , Camundongos , Complemento C5/antagonistas & inibidores , Desenho de Fármacos , Meia-Vida , Proteínas Inativadoras do Complemento/farmacologia , Proteínas Inativadoras do Complemento/química , Inativadores do Complemento/farmacologia , Inativadores do Complemento/farmacocinética , Inativadores do Complemento/química , HumanosRESUMO
Complement inhibitors are the mainstay of paroxysmal nocturnal hemoglobinuria (PNH) treatment. The anti-C5 monoclonal antibody eculizumab was the first treatment to improve hemolysis, thrombotic risk, and survival in PNH although at the price of a life-long intravenous fortnightly drug. Additionally, suboptimal response may occur in up to 2/3 of patients with persistent anemia due to incomplete control of intravascular hemolysis, development of upstream C3-mediated extravascular hemolysis (EVH), or concomitant bone marrow failure. Ravulizumab, a longer half-life anti-C5 developed from eculizumab, administered every 8 weeks, improved patient convenience, and reduced pharmacokinetic breakthrough hemolysis (BTH) by establishing more stable anti-C5 concentrations. More recently, several other anti-C5 compounds (crovalimab, pozelimab, tesidolumab, cemdisiran, zilucoplan, and coversin) are on study in clinical trials. Upstream inhibition of complement cascade was also explored with the anti-C3 pegcetacoplan, and with the alternative pathway inhibitors iptacopan (anti-factor B) and danicopan (anti-factor D). These drugs efficiently target EVH and are able to improve anemia and transfusion need in suboptimal responders to anti-C5. The route and schedule of administration (twice weekly subcutaneously for pegcetacoplan and twice or thrice oral daily dosing for iptacopan and danicopan, respectively) are very convenient but pose novel issues regarding adherence. Additionally, both anti-C5 and upstream inhibitors do not resolve the unmet need of pharmacodynamic BTH events due to complement amplifying conditions such as infections, traumas, and surgery. In this review, we will recapitulate PNH physiopathology, clinical presentation, and diagnosis and describe available and developing drugs that will lead to a precision medicine approach for this rare though heterogenous disease.
Assuntos
Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Hemoglobinúria Paroxística , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Inativadores do Complemento/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C5/antagonistas & inibidores , Hemólise/efeitos dos fármacosRESUMO
ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease of uncontrolled terminal complement activation leading to intravascular hemolysis, thrombotic events and increased morbidity and mortality. This phase 3, open-label, single-arm, multicenter study evaluated ravulizumab treatment in eculizumab-naive or -experienced pediatric patients (aged <18 years) with PNH over a 26-week primary evaluation period (PEP) and 4-year extension period (EP). Patients included in the study received weight-based intravenous ravulizumab dosing. Primary end points were pharmacokinetic and pharmacodynamic parameters to confirm complement component 5 (C5) inhibition by ravulizumab; secondary end points assessed the efficacy (including percentage change in lactate dehydrogenase levels over time) and safety of ravulizumab. Thirteen patients, 5 (38.5%) eculizumab-naive and 8 (61.5%) eculizumab-experienced, were enrolled. Ravulizumab Ctrough levels were above the pharmacokinetic threshold of 175 µg/mL in the PEP and EP except in 1 patient. At the end of the study, pre- and post-infusion mean ± standard deviation serum ravulizumab concentrations were 610.50 ± 201.53 µg/mL and 518.29 ± 109.67 µg/mL for eculizumab-naive and eculizumab-experienced patients, respectively. After the first ravulizumab infusion, serum-free C5 concentrations were <0.5 µg/mL in both cohorts until the end of the study (0.061 ± 0.021 µg/mL and 0.061 ± 0.018 µg/mL for eculizumab-naive and eculizumab-experienced patients, respectively). Compared with baseline, ravulizumab improved and maintained efficacy outcomes in both groups. Ravulizumab had an acceptable safety profile with no new safety signals identified, and provided immediate, complete, and sustained terminal complement inhibition, translating to clinical benefit for pediatric patients with PNH. This trial was registered at www.ClinicalTrials.gov as #NCT03406507.
Assuntos
Anticorpos Monoclonais Humanizados , Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Criança , Feminino , Masculino , Adolescente , Resultado do Tratamento , Pré-Escolar , Inativadores do Complemento/farmacocinética , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/efeitos adversos , Inativadores do Complemento/administração & dosagem , Complemento C5/antagonistas & inibidoresRESUMO
BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).
Assuntos
Anemia Hemolítica , Fator B do Complemento , Inativadores do Complemento , Hemoglobinas , Hemoglobinúria Paroxística , Humanos , Administração Oral , Anemia Hemolítica/complicações , Complemento C5/antagonistas & inibidores , Fator B do Complemento/antagonistas & inibidores , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/efeitos adversos , Inativadores do Complemento/uso terapêutico , Transfusão de Eritrócitos , Cefaleia/induzido quimicamente , Hemoglobinas/análise , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/etiologia , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder characterized by relapses of inflammation and demyelination primarily affecting the optic nerve and the spinal cord. C5 complement inhibition is an effective therapeutic approach in the treatment of NMOSD. In this systematic review and meta-analysis, we aimed to determine the role of C5 inhibitors in the treatment of patients with seropositive anti-aquaporin-4 antibody (AQP4+IgG) NMOSD. METHODS: This systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Relevant articles were systematically searched through Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases until October 6th, 2023. We included randomized clinical trials (RCTs) that investigated the treatment with C5 inhibitors compared to placebo in patients with seropositive NMOSD. The primary endpoint was the rates of first adjudicated relapse. Secondary endpoints included different disability and quality of life measures. The random-effects model was used for all statistical analyses. RESULTS: Two RCTs with a total of 201 patients were included. C5 inhibitors demonstrated significant reduction of first adjudicated relapse (risk ratio (RR) = 0.05, 95 % CI 0.01-0.15) and Hauser Ambulation Index (HAI) (mean difference (MD): -0.79, 95 % CI -1.27 to -0.31). There was no significant difference between the two groups in Expanded Disability Status Scale (EDSS) (MD -0.23, 95 % CI -0.54-0.08). C5 inhibitors significantly improved the mean change in EQ-5D index (MD 0.08, 95 % CI 0.01-0.14; P = 0.02); however, no significant difference was shown in the mean change in EQ-5D VAS (MD 3.79, 95 % CI -1.61 to 9.19; P = 0.17). Safety measures were comparable between C5 inhibitors and placebo. CONCLUSION: NMOSD Patients with AQP4+IgG receiving C5 inhibitors have lower rate of relapses and improved levels of disability and quality of life. Real-world studies are warranted to establish the long-term safety of C5 inhibitors.
Assuntos
Aquaporina 4 , Autoanticorpos , Neuromielite Óptica , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/imunologia , Humanos , Aquaporina 4/imunologia , Aquaporina 4/antagonistas & inibidores , Autoanticorpos/sangue , Complemento C5/antagonistas & inibidores , Complemento C5/imunologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Atypical-hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy often due to uncontrolled complement activation, characterized by high risk of end-stage kidney disease (ESKD). Eculizumab has improved the outcome, however, its efficacy varies among patients and its discontinuation is debated. METHODS: To identify characteristics associated with treatment response, we analyzed 244 aHUS patients referred to our center. Patients were classified according to the presence/absence of complement abnormalities and/or triggers at onset in 4 categories: (1) primary (complement abnormality without trigger), (2) secondary (trigger without complement abnormality), (3) combined (trigger and complement abnormality), (4) idiopathic (no trigger, no complement abnormality). Response to treatment was evaluated by comparing the response to eculizumab with that of conventional therapy. Short- and long-term outcomes were evaluated with the relapse rate after discontinuation of C5-inhibition. RESULTS: Patients had a better outcome with eculizumab compared to conventional treatment, with a response rate of 81.9% vs 56.9%, p < 0.001 and a long-term cumulative incidence of ESKD of 5.8% vs 22.5% (hazard ratio 0.25, 95% confidence interval: 0.10-0.80). The excellent global response was driven by the primary and combined groups (89.8% vs 54.0% and 89.3% vs 54.2%, respectively). The relapse rate following discontinuation of the C5-inhibitor was as high as 66.7% in the primary group, 18.7% in the combined, and 0% in the secondary and idiopathic groups. CONCLUSIONS: Our data show a better outcome in aHUS patients treated with C5-inhibition, particularly in the primary and combined forms, which have a high risk of relapse after discontinuation that is not observed in the secondary and idiopathic forms.
Assuntos
Anticorpos Monoclonais Humanizados , Síndrome Hemolítico-Urêmica Atípica , Complemento C5 , Humanos , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto , Complemento C5/antagonistas & inibidores , Resultado do Tratamento , Falência Renal Crônica/etiologia , Inativadores do Complemento/uso terapêutico , Estudos Retrospectivos , Adolescente , Adulto Jovem , Recidiva , Pessoa de Meia-Idade , Ativação do Complemento/efeitos dos fármacos , Criança , Fatores de Risco , Fatores de TempoRESUMO
Introduction: The complement system is a key component of the innate immune system, and its aberrant activation underlies the pathophysiology of various diseases. Zilucoplan is a macrocyclic peptide that binds and inhibits the cleavage/activation of human complement component 5 (C5). We present in vitro and ex vivo data on the mechanism of action of zilucoplan for the inhibition of C5 activation, including two clinically relevant C5 polymorphisms at R885. Methods: The interaction of zilucoplan with C5, including for clinical C5 R885 variants, was investigated using surface plasmon resonance (SPR), hemolysis assays, and ELISA. The interference of C5b6 formation by zilucoplan was investigated by native gel analysis and hemolysis assay. The permeability of zilucoplan in a reconstituted basement membrane was assessed by the partition of zilucoplan on Matrigel-coated transwell chambers. Results: Zilucoplan specifically bound human complement C5 with high affinity, competitively inhibited the binding of C5 to C3b, and blocked C5 cleavage by C5 convertases and the assembly of the cytolytic membrane attack complex (MAC, or C5b9). Zilucoplan fully prevented the in vitro activation of C5 clinical variants at R885 that have been previously reported to respond poorly to eculizumab treatment. Zilucoplan was further demonstrated to interfere with the formation of C5b6 and inhibit red blood cell (RBC) hemolysis induced by plasmin-mediated non-canonical C5 activation. Zilucoplan demonstrated greater permeability than a monoclonal C5 antibody in a reconstituted basement membrane model, providing a rationale for the rapid onset of action of zilucoplan observed in clinical studies. Conclusion: Our findings demonstrate that zilucoplan uses a dual mode of action to potently inhibit the activation of C5 and terminal complement pathway including wild-type and clinical R885 variants that do not respond to eculizumab treatment. These data may be relevant to the clinically demonstrated benefits of zilucoplan.
Assuntos
Ativação do Complemento , Complemento C5 , Hemólise , Humanos , Anticorpos Monoclonais , Complemento C5/antagonistas & inibidoresRESUMO
The human complement system plays a crucial role in immune defense. However, its erroneous activation contributes to many serious inflammatory diseases. Since most unwanted complement effector functions result from C5 cleavage into C5a and C5b, development of C5 inhibitors, such as clinically approved monoclonal antibody eculizumab, are of great interest. Here, we developed and characterized two anti-C5 nanobodies, UNbC5-1 and UNbC5-2. Using surface plasmon resonance, we determined a binding affinity of 119.9 pM for UNbC5-1 and 7.7 pM for UNbC5-2. Competition experiments determined that the two nanobodies recognize distinct epitopes on C5. Both nanobodies efficiently interfered with C5 cleavage in a human serum environment, as they prevented red blood cell lysis via membrane attack complexes (C5b-9) and the formation of chemoattractant C5a. The cryo-EM structure of UNbC5-1 and UNbC5-2 in complex with C5 (3.6 Å resolution) revealed that the binding interfaces of UNbC5-1 and UNbC5-2 overlap with known complement inhibitors eculizumab and RaCI3, respectively. UNbC5-1 binds to the MG7 domain of C5, facilitated by a hydrophobic core and polar interactions, and UNbC5-2 interacts with the C5d domain mostly by salt bridges and hydrogen bonds. Interestingly, UNbC5-1 potently binds and inhibits C5 R885H, a genetic variant of C5 that is not recognized by eculizumab. Altogether, we identified and characterized two different, high affinity nanobodies against human C5. Both nanobodies could serve as diagnostic and/or research tools to detect C5 or inhibit C5 cleavage. Furthermore, the residues targeted by UNbC5-1 hold important information for therapeutic inhibition of different polymorphic variants of C5.
Assuntos
Anticorpos Monoclonais , Complemento C5 , Anticorpos de Domínio Único , Humanos , Ativação do Complemento , Complemento C5/antagonistas & inibidores , Complemento C5/genética , Complexo de Ataque à Membrana do Sistema Complemento , Proteínas do Sistema Complemento/metabolismoRESUMO
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic disease driven by impaired complement regulation. Mutations in genes encoding the enzymes that build the GPI anchors are causative, with somatic mutations in the PIG-A gene occurring most frequently. As a result, the important membrane-bound complement regulators CD55 and CD59 are missing on the affected hematopoietic stem cells and their progeny, rendering those cells vulnerable to complement attack. Immune escape mechanisms sparing affected PNH stem cells from removal are suspected in the PNH pathogenesis, but molecular mechanisms have not been elucidated. We hypothesized that exuberant complement activity in PNH results in enhanced immune checkpoint interactions, providing a molecular basis for the potential immune escape in PNH. In a series of PNH patients, we found increased expression levels of the checkpoint ligand programmed death-ligand 1 (PD-L1) on granulocytes and monocytes, as well as in the plasma of PNH patients. Mechanistically, we demonstrate that complement activation leading to the decoration of particles/cells with C3- and/or C4-opsonins increased PD-L1 expression on neutrophils and monocytes as shown for different in vitro models of classical or alternative pathway activation. We further establish in vitro that complement inhibition at the level of C3, but not C5, inhibits the alternative pathway-mediated upregulation of PD-L1 and show by means of soluble PD-L1 that this observation translates into the clinical situation when PNH patients are treated with either C3 or C5 inhibitors. Together, the presented data show that the checkpoint ligand PD-L1 is increased in PNH patients, which correlates with proximal complement activation.
Assuntos
Antígeno B7-H1/metabolismo , Ativação do Complemento/imunologia , Complemento C3/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Hemoglobinúria Paroxística/patologia , Antígeno B7-H1/sangue , Antígenos CD55/genética , Antígenos CD59/genética , Complemento C3/imunologia , Complemento C5/imunologia , Granulócitos/metabolismo , Células-Tronco Hematopoéticas/citologia , Hemoglobinúria Paroxística/imunologia , Humanos , Evasão da Resposta Imune/imunologia , Proteínas de Membrana/genética , Monócitos/metabolismoRESUMO
Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of Bacillus anthracis, leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis. Similar to aHUS anthrax patients, PGN induces an initial hematocrit elevation followed by progressive hemolytic anemia and associated renal failure. Etiologically, PGN induces erythrolysis through direct excessive activation of all three complement pathways. Blunting terminal complement activation with a C5 neutralizing peptide prevented the progressive deposition of membrane attack complexes on red blood cells (RBC) and subsequent intravascular hemolysis, heme cytotoxicity, and acute kidney injury. Importantly, C5 neutralization did not prevent immune recognition of PGN and shifted the systemic inflammatory responses, consistent with improved survival in sepsis. Whereas PGN-induced hemostatic dysregulation was unchanged, C5 inhibition augmented fibrinolysis and improved the thromboischemic resolution. Overall, our study identifies PGN-driven complement activation as the pathologic mechanism underlying hemolytic anemia in anthrax and likely other gram-positive infections in which PGN is abundantly represented. Neutralization of terminal complement reactions reduces the hemolytic uremic pathology induced by PGN and could alleviate heme cytotoxicity and its associated kidney failure in gram-positive infections.
Assuntos
Injúria Renal Aguda/prevenção & controle , Anemia Hemolítica/prevenção & controle , Bacillus anthracis/química , Parede Celular/química , Complemento C5/antagonistas & inibidores , Peptidoglicano/toxicidade , Sepse/complicações , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Anemia Hemolítica/etiologia , Anemia Hemolítica/patologia , Animais , Antraz/microbiologia , Antraz/patologia , Feminino , Hemólise , Masculino , Papio , Sepse/induzido quimicamenteRESUMO
BACKGROUND: ABP 959 is one of the first proposed biosimilars to eculizumab reference product (RP), a recombinant IgG2/4Æ monoclonal antibody (mAb) that binds human C5 complement protein and inhibits C5 cleavage to C5a and C5b, preventing the generation of the terminal complement complex C5b-9. Eculizumab RP is approved for the treatment of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis in patients who are anti-acetylcholine receptor antibody positive, and neuromyelitis optica spectrum disorder in patients who are anti-aquaporin-4 antibody positive. OBJECTIVES: The objective of this work was to comparatively assess analytical (structural and functional) similarity between ABP 959 and eculizumab RP using sensitive, state-of-the art analytical methods capable of detecting minor differences in product quality attributes. METHODS: Comprehensive analytical (structural and functional) characterization utilizing orthogonal techniques was performed using multiple lots of ABP 959 and eculizumab RP over several years applying > 40 state-of-the-art assays. Comparisons were performed to investigate the primary structure and post-translational modifications including glycans, higher-order structure, particles and aggregates, product-related structures and impurities, thermal stability and forced degradation, general properties, and biological properties mediated by target binding. RESULTS: Results confirmed that ABP 959 had the same amino acid sequence, similar primary structure, higher-order structure, post-translational profiles, and the same protein content and concentration (e.g., ABP 959: 9.4-10.0; eculizumab EU: 9.4-10.0; eculizumab US: 9.3-10.3 mg/mL) as well as biological activity as eculizumab RP. CONCLUSIONS: Based on these results, it can be concluded that ABP 959 is analytically similar to eculizumab RP.
Assuntos
Anticorpos Monoclonais Humanizados , Medicamentos Biossimilares , Complemento C5/antagonistas & inibidores , Hemoglobinúria Paroxística , HumanosAssuntos
Inativadores do Complemento/efeitos adversos , Hemoglobinúria Paroxística/tratamento farmacológico , Sobrecarga de Ferro/induzido quimicamente , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Ferritinas/sangue , Hemoglobinúria Paroxística/sangue , Hemólise/efeitos dos fármacos , Humanos , Sobrecarga de Ferro/sangueRESUMO
INTRODUCTION: Generalized myasthenia gravis (gMG) is an autoimmune disorder in which pathogenic autoantibodies damage the neuromuscular junction, causing disabling or life-threatening muscle weakness. Most treatments nonspecifically inhibit aspects of the immune system, do not directly address the causal mechanisms of tissue damage, and often have side-effect profiles that negatively impact patients. Understanding of the central pathogenic role of the complement cascade in gMG is advancing, and a new complement-targeting treatment is under investigation. AREAS COVERED: We provide an overview of gMG etiology, the complement cascade, current treatments, and the investigational gMG therapy zilucoplan. Zilucoplan is a small, subcutaneously administered, macrocyclic peptide that inhibits cleavage of complement component C5 and the subsequent formation of the membrane attack complex. EXPERT OPINION: In a randomized, double-blind, placebo-controlled, phase 2 clinical trial, zilucoplan demonstrated clinically meaningful complement inhibition in patients with acetylcholine receptor-positive gMG. Zilucoplan, a first-of-its-kind cyclic peptide targeting C5, appears to be a therapeutic option for the treatment of gMG based on available pharmacokinetic/pharmacodynamic data and phase 1 and 2 efficacy, safety, and tolerability data with limited long-term follow-up. Zilucoplan use earlier in the treatment paradigm would be suitable in this population should phase 3 efficacy and safety data be equally favorable.