RESUMO
Interest in the detection of specific anti-Pneumocystis jirovecii antibodies has emerged as less-invasive alternative diagnostic approaches. Here is presented the performance of an ELISA based on a recombinant synthetic multi-epitope kexin 1 (Kex1) antigen of P. jirovecii, previously developed. Results showed that IgM anti-Kex1 levels were found significantly increased in patients with Pneumocystis pneumonia (PcP) compared with non-PcP cases (p < 0.001), allowing a diagnostic performance of PcP with a 70.8% sensitivity and a 75.0% specificity. These results suggest that this Kex1-based ELISA is a promising tool toward the serodiagnosis of PcP when the standard methods are difficult to perform.
Assuntos
Anticorpos Antifúngicos/imunologia , Pneumocystis carinii/imunologia , Pneumonia por Pneumocystis/microbiologia , Área Sob a Curva , Ensaio de Imunoadsorção Enzimática , Humanos , Pneumonia por Pneumocystis/sangue , Pró-Proteína Convertases/química , Pró-Proteína Convertases/imunologia , Estudos Retrospectivos , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/imunologia , Sensibilidade e EspecificidadeRESUMO
Purpose: Proprotein convertase subtilisin/kexin type 4 (PCSK4, a 54-kDa protease) is expressed in the plasma membrane of the acrosome in human spermatozoa. It plays a critical role in penetrating the zona pellucida. Synthesis of human anti-PCSK4 might be important for novel male immunocontraception. Materials and Methods: We used semen from adult males as the source of antigen (acrosomal PCSK4). Isolation and antigen characterization were done by immunohistochemistry followed by electrophoresis. Purification of PCSK4 was done by the electroelution method, followed by immunization with an animal model (Oryctolagus cuniculus). Antibody was collected, purified, and tested by using Western blot and dot blot. Antibody in vitro potential testing was performed on human spermatozoa by laser scanning microscopy with rhodamine stain under a light microscope and on rat spermatozoa. Results: Human anti-PCSK4 bound with PCSK4 on the head of human spermatozoa and could interfere with rat spermatozoa activity to penetrate the oocyte. Conclusions: The result of this study can be used as a basis to develop new immunocontraceptives targeted towards males. This study shows that antibodies from induction of PCSK4 from spermatozoa may hinder fertilization.
Assuntos
Antígenos/imunologia , Anticoncepção Imunológica/métodos , Pró-Proteína Convertases/imunologia , Espermatozoides/enzimologia , Subtilisinas/imunologia , Adulto , Animais , Humanos , Masculino , Modelos Animais , Pró-Proteína Convertases/síntese química , Coelhos , Subtilisinas/síntese químicaRESUMO
Heterozygous familial hypercholesterolemia (HeFH) is characterized by a prevalence of 1/200 (higher than 1/500 as previously estimated): based on this updated prevalence, in Italy there are about 250-300 000 subjects with HeFH. Patients with HeFH are significantly underdiagnosed (in Italy only 4-5% of total estimated HeFH are properly diagnosed), undertreated (only 1 in 5 to 10 HeFH at target for LDL-cholesterol), and characterized by a high or very high cardiovascular risk. There are simple criteria for the diagnosis of familial hypercholesterolemia such as those issued by the Dutch Lipid Clinic Network (DLCN), easy to implement both in general practice as well as by the specialists. Genetic diagnosis is strongly suggested to support the diagnosis of familial hypercholesterolemia. Lipid-lowering therapy with high dose of highly effective statins, often associated with ezetimibe, should be initiated immediately at diagnosis in adults and at age 8-10 years in childhood. Evolocumab and alirocumab are monoclonal antibodies against PCSK9. They are a highly innovative lipid-lowering approach, characterized by a good safety profile and a remarkable LDL-cholesterol lowering effect when associated with the maximally tolerated dose of statins plus ezetimibe. Studies with alirocumab and evolocumab in HeFH patients show a further LDL-cholesterol decrease by 50-60% vs intensive lipid-lowering therapy with statins ± ezetimibe, with 70-80% of HeFH patients achieving their LDL-cholesterol targets.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/etiologia , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/genética , Linhagem , Pró-Proteína Convertase 9 , Fatores de RiscoRESUMO
Acute coronary syndromes (ACS) are a major health problem both in industrialized countries and in developing ones, and a leading cause of death and disability. The pathogenesis of ACS is multifactorial and complex, with approximately 65-70% of cases caused by the abrupt occlusion of a coronary vessel. This usually occurs as a result of thrombus formation over a vulnerable, lipid-rich atherosclerotic plaque, which undergoes rupture or erosion. High levels of LDL-cholesterol (LDL-C) are a well known risk factor for the development of atherosclerosis, and the reduction in plasma LDL-C is a fundamental treatment both in primary and secondary prevention. Statins are the most extensively used lipid-lowering drugs. They have been associated with reduced progression of coronary atherosclerosis and a decreased incidence of new ACS episodes or post-ACS major cardiovascular events. For ACS patients, the European Society of Cardiology (ESC) has suggested an early treatment - starting with the acute phase - together with a well defined target value of LDL-C level, which should be achieved during the follow-up. While statin therapy has significantly lowered cardiovascular risk, several cardiovascular events are still not prevented and a residual risk remains also after intensive therapy. In addition, a significant proportion of high-risk patients do not achieve the LDL-C target recommended by the ESC guidelines or present with statin intolerance, which does not allow a continuative and effective treatment. This is the main reason why innovative lipid-lowering therapies might become a new opportunity in ACS patients. The recently published results of the IMPROVE-IT trial have shown that the association statin + ezetimibe is superior to statin alone in preventing cardiovascular death, non-fatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization and stroke in a population of medium to high-risk patients stabilized after ACS. Monoclonal antibodies targeting human PCSK9 are currently being tested on top of statins in patients with ACS, to investigate their superiority in reducing major cardiovascular adverse events as compared with statins alone at the maximally tolerated dose. The results, expected for 2017, will hopefully benefit the treatment of patients in secondary prevention and contribute to a better outcome of ACS patients worldwide.
Assuntos
Síndrome Coronariana Aguda/complicações , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Síndrome Coronariana Aguda/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Previsões , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Fatores de Risco , Serina Endopeptidases/imunologiaRESUMO
Evolocumab (Repatha(®)) is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered subcutaneously at a dosage of 140 mg every 2 weeks or 420 mg once monthly. Across 12-week phase III trials in patients with primary hypercholesterolemia or mixed dyslipidemia, evolocumab was more effective than placebo (treatment difference -54.8 to -76.3%) and/or ezetimibe (treatment difference -36.9 to -47.2%) at reducing low-density lipoprotein cholesterol (LDL-C) levels, including when added to statin therapy, when administered to statin-intolerant patients, when administered as monotherapy, and in patients with heterozygous familial hypercholesterolemia who were receiving statins with or without other lipid-lowering drugs. Evolocumab also significantly lowered LDL-C levels (treatment difference of ≈30% vs. placebo) in patients with homozygous familial hypercholesterolemia when added to statins with or without ezetimibe in a 12-week phase III trial. The efficacy of evolocumab was maintained in the longer term, and it was well tolerated. In conclusion, subcutaneous evolocumab is a valuable new treatment for use in primary hypercholesterolemia or mixed dyslipidemia and homozygous familial hypercholesterolemia, particularly in patients unable to reach LDL-C goals despite treatment with statins with or without other lipid-lowering therapies and in patients who do not tolerate or are not able to receive statins.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , LDL-Colesterol/sangue , Ezetimiba/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/efeitos adversos , Hipolipemiantes/farmacologia , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologiaRESUMO
Monoclonal antibodies (mAbs) to proprotein convertase subtilisin/kexin type 9 (PCSK-9) can further lower LDL-C by ≥60% in statin-treated patients. Preliminary data suggest they may reduce cardiovascular (CVD) events. Ongoing PCSK-9 mAb cardiovascular outcomes trials could provide the opportunity to determine whether a "legacy effect" similar to that observed for statins will occur over the post-trial observation period. We hypothesize these trials could demonstrate that (1) very aggressive LDL-C lowering with PCSK-9 mAbs added to background statin therapy will induce extensive atherosclerosis stabilization and regression in the large majority of treated patients, and (2) continued maintenance therapy with high intensity statin therapy (with or without ezetimibe) should then inhibit new plaque formation, with a long-term prevention of CVD events. The necessity of expensive lifetime treatment with PCSK-9 inhibitors could then be avoided in all but a small subset of patients who could benefit from longer treatment.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Aterosclerose/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Placa Aterosclerótica , Pró-Proteína Convertases/antagonistas & inibidores , Prevenção Secundária/métodos , Inibidores de Serina Proteinase/uso terapêutico , Animais , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/etiologia , Biomarcadores/sangue , LDL-Colesterol/sangue , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/enzimologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Terapia de Alvo Molecular , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Pró-Proteína Convertases/metabolismo , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo , Resultado do TratamentoRESUMO
OBJECTIVE: To review the mechanism of action for PCSK9 monoclonal antibodies and critically evaluate the therapeutic potential of evolocumab and alirocumab in the treatment of hypercholesterolemia. DATA SOURCES: Ovid MEDLINE search from 1980 to August 2015 using the terms PCSK9, evolocumab, and alirocumab with forward and backward citation tracking. STUDY SELECTION AND DATA EXTRACTION: English-language trials and studies assessing the mechanism, efficacy, or safety of PCSK9 monoclonal antibodies were included. DATA SYNTHESIS: PCSK9 monoclonal antibodies have a potent ability to reduce low-density lipoprotein (LDL) by almost 50% in controlled trials: -47.49% (95% CI = -69.6% to -25.4%). They have an acceptable safety profile with no significant elevations in Creatine Kinase (CK) (odds ratio [OR] = 0.72; 95% CI = 0.54 to 0.96) or serious adverse events (OR = 1.01; 95% CI = 0.87 to 1.18), and preliminary evidence suggests reductions in myocardial infarction (OR = 0.49; 95% CI = 0.26 to 0.93). Although it is effective in several familial hypercholesterolemia (FH) patient types, it does not work in homozygous patients with dual allele LDL receptor negative polymorphisms or those who are homozygous for autosomal recessive hypercholesterolemia. CONCLUSIONS: Although not preferred over statins because of limited clinical trial evidence of cardiovascular event reductions, dosing convenience, and expense, PCSK9 monoclonal antibodies will have a prominent role to play in the treatment of hypercholesterolemia, especially in patients needing large LDL reductions, including patients with many types of FH.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Anticorpos Monoclonais Humanizados , LDL-Colesterol/sangue , Humanos , Hipercolesterolemia/genética , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Infarto do Miocárdio/prevenção & controle , Guias de Prática Clínica como Assunto , Pró-Proteína Convertase 9 , Receptores de LDL/genética , Resultado do Tratamento , Hiperlipoproteinemia Tipo IIIRESUMO
Lilly PCSK9 antibody LY3015014 (LY) is a monoclonal antibody (mAb) that neutralizes proprotein convertase subtilisin-kexin type 9 (PCSK9). LY decreases LDL cholesterol in monkeys and, unlike other PCSK9 mAbs, does not cause an accumulation of intact PCSK9 in serum. Comparing the epitope of LY with other clinically tested PCSK9 mAbs, it was noted that the LY epitope excludes the furin cleavage site in PCSK9, whereas other mAbs span this site. In vitro exposure of PCSK9 to furin resulted in degradation of PCSK9 bound to LY, whereas cleavage was blocked by other mAbs. These other mAbs caused a significant accumulation of serum PCSK9 and displayed a shorter duration of LDL-cholesterol lowering than LY when administered to mice expressing the WT human PCSK9. In mice expressing a noncleavable variant of human PCSK9, LY behaved like a cleavage-blocking mAb, in that it caused significant PCSK9 accumulation, its duration of LDL lowering was reduced, and its clearance (CL) from serum was accelerated. Thus, LY neutralizes PCSK9 and allows its proteolytic degradation to proceed, which limits PCSK9 accumulation, reduces the CL rate of LY, and extends its duration of action. PCSK9 mAbs with this property are likely to achieve longer durability and require lower doses than mAbs that cause antigen to accumulate.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/farmacologia , Pró-Proteína Convertases/antagonistas & inibidores , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacocinética , LDL-Colesterol/sangue , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Furina/química , Meia-Vida , Humanos , Hipercolesterolemia/tratamento farmacológico , Macaca fascicularis , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Ligação Proteica , Proteólise , Serina Endopeptidases/imunologia , Resultado do TratamentoRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that controls cholesterol homeostasis by enhancing endosomal and lysosomal degradation of the low-density lipoprotein receptor (LDL-R). Mutations that cause increased activity of PCSK9 are associated with hypercholesterolemia, atherosclerosis and early cardiovascular disease (CVD), whereas individuals with loss-of-function mutations in PCSK9 are apparently healthy but are hypocholesterolemic and have a dramatically decreased risk of CVD. In this study, we generated virus-like particle (VLP)-based vaccines targeting PCSK9. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides. A vaccine targeting PCSK9 may, therefore, be an attractive alternative to monoclonal antibody-based therapies.
Assuntos
Colesterol/sangue , Pró-Proteína Convertases/antagonistas & inibidores , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Animais , Autoanticorpos/sangue , Bacteriófagos/genética , Portadores de Fármacos , Feminino , Imunoglobulina G/sangue , Macaca , Masculino , Camundongos Endogâmicos BALB C , Fosfolipídeos/sangue , Pró-Proteína Convertases/imunologia , Resultado do Tratamento , Triglicerídeos/sangue , Vacinas de Partículas Semelhantes a Vírus/genéticaRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9), which involves in low-density lipoprotein cholesterol (LDL-C) metabolism by interacting with the LDL receptor, is considered as a potent therapeutic target for treating hypercholesterolemia. Here, a fab antibody phage display library was constructed and employed for bio-panning against recombinant PCSK9. A Fab fragment (designated PA4) bound with high affinity to PCSK9 was isolated after four rounds of panning. The fully human antibody IgG1-PA4 bound specifically to PCSK9 with nanomolar affinity. In vitro, IgG1-PA4 inhibited PCSK9 binding to LDLR and attenuated PCSK9-mediated degradation of LDLR on the HepG2 cell surface. In C57BL/6 mice, administration of IgG1-PA4 at 30 mg/kg increased hepatic LDLR protein levels by as much as 3 fold when compared with control. Taken together, these results suggested that the IgG1-PA4 can be served as a potential candidate for the treatment of hypercholesterolemia by inhibiting PCSK9-mediated degradation of cell surface LDLRs.
Assuntos
Anticorpos/imunologia , Bacteriófagos/genética , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Animais , Especificidade de Anticorpos , Ensaio de Imunoadsorção Enzimática , Células Hep G2 , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Proteólise , Receptores de LDL/metabolismo , Serina Endopeptidases/genéticaRESUMO
BACKGROUND: Proprotein convertase subtilisin/kexin9 (PCSK9) monoclonal antibody significantly reduces low-density lipoprotein cholesterol level in patients with hypercholesterolemia. The goal of this study was to review recently reported randomized controlled trials to investigate the therapeutic effects and safety of PCSK9 inhibitors. METHODS AND RESULTS: The clinical randomized controlled trials published from inception to March 19, 2015 were identified from The Cochrane Library databases, PUBMED, and EBASE. Randomized controlled trials of at least 8 weeks duration using PCSK9 inhibitors in treating patients with hypercholesterolemia were included. Mean difference (MD) with a 95% CI was used to calculate the continuous data, the standardized mean difference with a 95% CI was used when the unit was not unified, and risk ratio with a 95% CI was used for dichotomous data. After screening, 20 trials fulfilled the inclusion criteria. PCSK9 inhibitors significantly decreased the levels of low-density lipoprotein cholesterol (MD=-65.29 mg/dL, 95% CI: -72.08 to -58.49), total cholesterol (MD=-60.04 mg/dL, 95% CI: -69.95 to -50.13), triglycerides (MD=-12.21 mg/dL, 95% CI: -16.21 to -8.22) and apolipoprotein-B (MD=-41.01 mg/dL, 95% CI: -46.07 to -35.94), lipoprotein(a) (standardized mean difference=-0.94, 95% CI: -1.12 to -0.77) and increased the levels of high-density lipoprotein cholesterol (MD=3.40 mg/dL, 95% CI: 3.12 to 3.68) and apolipoprotein-A1 (MD=6.75 mg/dL, 95% CI: 4.64 to 8.86). There was no significant difference in the incidence of treatment-emergent adverse events (risk ratio=1.01, 95% CI: 0.98 to 1.04), serious treatment-emergent adverse events (risk ratio=1.01, 95% CI: 0.88 to 1.17), and the discontinuation of treatment between the 2 groups (risk ratio=1.07, 95% CI: 0.86 to 1.34). CONCLUSIONS: The meta-analysis indicated that PCSK9 inhibitors had a strong effect in lowering low-density lipoprotein cholesterol and other lipid levels with satisfactory safety and tolerability in patients with hypercholesterolemia.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/sangue , Humanos , Lipídeos/sangue , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Serina Endopeptidases/imunologia , Resultado do TratamentoAssuntos
Anticorpos Monoclonais/uso terapêutico , Doença da Artéria Coronariana/terapia , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/imunologia , Terapia Genética , Humanos , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/antagonistas & inibidores , Pró-Proteína Convertases/genética , RNA Interferente Pequeno/uso terapêutico , Serina Endopeptidases/genética , Terapias em Estudo/métodos , Terapias em Estudo/tendênciasRESUMO
Reducing plasma levels of low-density lipoprotein cholesterol (LDL-c) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, a substantial proportion of patients fail to achieve acceptable LDL-c levels with currently available lipid-lowering drugs. Over the last decade, inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) has emerged as a promising target to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the LDL receptor for lysosomal degradation. Inhibition of PCSK9 increases expression of the LDL receptor. This observation has led to the development of a number of approaches to directly target PCSK9. Three monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials involving various patient categories on different background lipid lowering therapies. Current evidence shows reductions in LDL cholesterol levels of up to 70%, independent of background statin therapy. The results of phase 3 trials will demonstrate the long-term efficacy and safety of PCSK9 inhibition, and will indicate whether LDL-c lowering induced by this novel approach translates into beneficial effects on CVD outcome.
Assuntos
Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/enzimologia , Terapia de Alvo Molecular/métodos , Pró-Proteína Convertases , Animais , Anticorpos Monoclonais/imunologia , Inativação Gênica , Humanos , Hipercolesterolemia/genética , Pró-Proteína Convertases/antagonistas & inibidores , Pró-Proteína Convertases/deficiência , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/imunologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêuticoRESUMO
The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to the lysosome for degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation and a subsequent increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDL-C metabolism has been discovered in 2003, there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those, the PCSK9 antibodies are the furthest in development, with multiple phase III and cardiovascular endpoint trials already underway. These fully human monoclonal antibodies have been extensively studied in a wide range of subjects such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia. PCSK9 antibodies have shown to be associated with a consistent robust additional decrease in LDL-C concentrations of around 50-70%. If the safety data from the ongoing phase III trials remain as reassuring as the data available till now, PCSK9 antibodies are going to offer a new, powerful therapeutic option to decrease LDL-C concentrations and hopefully cardiovascular risk.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Animais , Anticorpos Monoclonais/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/enzimologia , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Pró-Proteína Convertases/metabolismo , Fatores de Risco , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo , Resultado do TratamentoRESUMO
Low-density lipoprotein cholesterol (LDL-C) reduction with statins is the cornerstone of atherosclerotic cardiovascular disease (CVD) prevention. The LDL-C lowering non-statin therapy ezetimibe also modestly reduces CVD risk when added to statin therapy. There remains a clinical need for additional LDL-C lowering agents to reduce CVD risk in patients with genetic hypercholesterolemia, statin intolerance, or who are at high risk due to clinical CVD or diabetes. In clinical trials, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition using monoclonal antibodies has demonstrated robust LDL-C lowering efficacy of 50-65% and a favorable safety profile. These agents are a promising therapeutic strategy for addressing the unmet needs for additional CVD risk reduction. Regulatory approval for PCSK9 monoclonal antibodies may occur in the near future, and additional agents for PCSK9 inhibition are under development. This review focuses on the mechanism of LDL-C reduction using PCSK9 inhibition, as well as the phase I to III clinical trials of PCSK9 inhibitors. Results of the ongoing phase III CVD outcome trials are eagerly awaited.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Inibidores Enzimáticos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Animais , Anticorpos Monoclonais/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Inibidores Enzimáticos/efeitos adversos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/enzimologia , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Pró-Proteína Convertases/metabolismo , Medição de Risco , Fatores de Risco , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo , Resultado do TratamentoRESUMO
Hyperlipidemia is a predominant risk factor for cardiovascular disease (CVD). Statins have been successfully used to treat patients with dyslipidemia and decrease the events of CVD in addition to application of various other non-statin-lowering cholesterol agents, such as ezetimibe and niacin. However, there are still residual risks in patients with atherosclerotic CVD. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9), which was first identified in 2003, has been suggested to play an important role in the metabolism of low-density lipoprotein cholesterol (LDL-C). PCSK9 degrades the LDL-receptor, which may be pharmacologically targeted to improve the lipoprotein profile and future cardiovascular outcomes in patients with dyslipidemia. Several approaches to inhibiting PCSK9 activity have been theoretically proposed. Among them, monoclonal antibodies have been considered as the most promising strategy because of their large effect on lowering lipids as monotherapy and in combination with statins or ezetimibe. In this review, we mainly focus on the current status of monoclonal antibodies of PCSK9 and clinical trial results for an update on clinical application of monoclonal antibodies of PCSK9. The particular effects of monoclonal antibodies of PCSK9 on lipid profiles are also discussed.