RESUMO
PURPOSE: The aim of this study was to develop a two-pore minimum physiologically-based pharmacokinetic (mPBPK) model in describing the pharmacokinetic (PK) of therapeutic monoclonal antibody (TMAb) in human subjects. METHODS: PK data used in this study were endogenous/exogenous native IgG and two TMAbs (palivizumab and Motavizumab-YTE) in normal volunteer or familial hypercatabolic hypoproteinemia (FIHH) patient. Several important components were implemented to overcome the limitations of the early mPBPK model, e.g. two-pore model to describe the transcapillary transport of IgG from vascular to interstitial space. Six mPBPK models with different osmotic reflection coefficient (OFC) of transcapillary transport, endocytosis rates (ETR) and plasma clearance for the TMAbs/IgG were tested and the best model was selected using AICc values. RESULTS: The final model consisted of different OFC and ETR values for native IgG and TMAbs, supporting the hypothesis that the dynamics in the endosomal space had an important role in the compliant FcRn salvage mechanism to determine the clearance of TMAbs. The estimated FcRn concentration of FIHH subjects was 2.72 µmol/l. The final two-pore mPBPK model has a better performance for native IgG than previously developed mPBPK model. CONCLUSIONS: The final two-pore mPBPK model not only overcome the limitations of the early mPBPK model but also has a better performance to describe the disposition of the IgG antibody in human subjects.
Assuntos
Anticorpos Monoclonais/farmacocinética , Permeabilidade Capilar , Imunoglobulina G/farmacologia , Erros Inatos do Metabolismo/tratamento farmacológico , Modelos Biológicos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacocinética , Capilares/metabolismo , Endocitose , Meia-Vida , Voluntários Saudáveis , Humanos , Imunoglobulina G/uso terapêutico , Mucosa Intestinal/irrigação sanguínea , Mucosa Intestinal/metabolismo , Taxa de Depuração Metabólica , Palivizumab/farmacocinéticaRESUMO
Monoclonal antibodies (mAbs) therapeutics are the largest and fastest growing class of biologic drugs, amongst which, the vast majority are immunoglobulin G1 (IgG1). Their antigen binding abilities are used for the treatment of immunologic diseases, cancer therapy, reversal of drug effects, and targeting viruses and bacteria. The high importance of therapeutic mAbs and their derivatives has called for the generation of well-characterized standards for method development and calibration. One such standard, the NISTmAb RM 8621 based on the antibody motavizumab, has been developed by the National Institute of Standards and Technologies (NIST) in the US. Here, we present the resonance assignment of the single chain variable fragment, NISTmAb-scFv, that was engineered by linking the variable domains of the heavy and light chains of the NISTmAb. Also, addition of a peptide, corresponding to the target antigen of motavizumab, to samples of NISTmAb-scFv has induced chemical shift perturbations on residues lining the antigen binding interface thereby indicating proper folding of the NISTmAb-scFv.
Assuntos
Produtos Biológicos , Anticorpos de Cadeia Única , Anticorpos Monoclonais/química , Imunoglobulina G/química , Ressonância Magnética Nuclear BiomolecularRESUMO
INTRODUCTION: The REGAL (RSV Evidence - A Geographical Archive of the Literature) series has provided a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This seventh and final publication covers the past, present and future approaches to the prevention and treatment of RSV infection among infants and children. METHODS: A systematic review was undertaken of publications between January 1, 1995 and December 31, 2017 across PubMed, Embase and The Cochrane Library. Studies reporting data on the effectiveness and tolerability of prophylactic and therapeutic agents for RSV infection were included. Study quality and strength of evidence (SOE) were graded using recognized criteria. A further nonsystematic search of the published literature and Clinicaltrials.gov on antiviral therapies and RSV vaccines currently in development was also undertaken. RESULTS: The systematic review identified 1441 studies of which 161 were included. Management of RSV remains centered around prophylaxis with the monoclonal antibody palivizumab, which has proven effective in reducing RSV hospitalization (RSVH) in preterm infants < 36 weeks' gestational age (72% reduction), children with bronchopulmonary dysplasia (65% reduction), and infants with hemodynamically significant congenital heart disease (53% reduction) (high SOE). Palivizumab has also shown to be effective in reducing recurrent wheezing following RSVH (high SOE). Treatment of RSV with ribavirin has conflicting success (moderate SOE). Antibodies with increased potency and extended half-life are currently entering phase 3 trials. There are approximately 15 RSV vaccines in clinical development targeting the infant directly or indirectly via the mother. CONCLUSION: Palivizumab remains the only product licensed for RSV prophylaxis, and only available for high-risk infants. For the general population, there are several promising vaccines and monoclonal antibodies in various stages of clinical development, with the aim to significantly reduce the global healthcare impact of this common viral infection. FUNDING: AbbVie.
RESUMO
Respiratory syncytial virus (RSV) infection is a leading cause of hospitalization and mortality in young children. Protective therapy options are limited. Currently, palivizumab, a monoclonal IgG1 antibody, is the only licensed drug for RSV prophylaxis, although other IgG antibody candidates are being evaluated. However, at the respiratory mucosa, IgA antibodies are most abundant and act as the first line of defense against invading pathogens. Therefore, it would be logical to explore the potential of recombinant human IgA antibodies to protect against viral respiratory infection, but very little research on the topic has been published. Moreover, it is unknown whether human antibodies of the IgA isotype are better suited than those of the IgG isotype as antiviral drugs to combat respiratory infections. To address this, we generated various human IgA antibody formats of palivizumab and motavizumab, two well-characterized human IgG1 anti-RSV antibodies. We evaluated their efficacy to prevent RSV infection in vitro and in vivo and found similar, but somewhat decreased efficacy for different IgA subclasses and formats. Thus, reformatting palivizumab or motavizumab into IgA reduces the antiviral potency of either antibody. Moreover, our results indicate that the efficacy of intranasal IgA prophylaxis against RSV infection in human FcαRI transgenic mice is independent of Fc receptor expression.
Assuntos
Anticorpos Monoclonais Humanizados , Anticorpos Antivirais , Imunoglobulina A , Imunoglobulina G , Palivizumab , Infecções por Vírus Respiratório Sincicial , Vírus Sinciciais Respiratórios/imunologia , Animais , Anticorpos Monoclonais Humanizados/genética , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/farmacologia , Linhagem Celular , Humanos , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina A/farmacologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Palivizumab/genética , Palivizumab/imunologia , Palivizumab/farmacologia , Engenharia de Proteínas , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/imunologiaRESUMO
Respiratory syncytial virus (RSV) accounts for about 20% of all respiratory infections in children below the age of 5 y. It is associated with up to 63% of all acute respiratory infections and up to 81% of all viral lower respiratory tract infections causing hospitalization in infants and young children. RSV leads to seasonal epidemics between November and April in the northern hemisphere. Most severe infections (RSV accounts for 50 to 80% of all cause bronchiolitis) affect infants younger than 6 months of age and high-risk infants including those born preterm with or without bronchopulmonary dysplasia and those with hemodynamically significant congenital heart disease up to an age of 24 months. Palivizumab, a highly potent RSV-neutralizing monoclonal antibody (Mab), has been licensed in 1998 for prophylactic use to prevent RSV associated hospitalizations in high-risk infants. This Mab is given by monthly intramuscular injection at a dose of 15 mg/kg over the RSV season (up to 5 times). Palivizumab proved to be safe and well-tolerated in this population. Concerns have been raised regarding cost-effectiveness of palivizumab and thus, palivizumab prophylaxis is mainly limited to selected high-risk infants for the first RSV season. Long-lasting Mabs will be the next future approach in the prophylaxis of RSV hospitalization until a vaccine is developed.
Assuntos
Antivirais , Palivizumab , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/economia , Análise Custo-Benefício , Feminino , Hospitalização , Humanos , Lactente , Recém-Nascido , Masculino , Palivizumab/administração & dosagem , Palivizumab/efeitos adversos , Palivizumab/economia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Fatores de RiscoRESUMO
Post-infectious immunity to respiratory syncytial virus (RSV) infection results in limited protection as evidenced by the high rate of infant hospitalization in the face of high titer, maternally derived RSV-specific antibodies. By contrast, RSV fusion (F) glycoprotein antigenic site II humanized monoclonal antibodies, palivizumab and motavizumab, have been shown to reduce RSV-related hospitalization in infants. Immunogenicity and efficacy studies were conducted in cotton rats comparing a recombinant RSV F nanoparticle vaccine with palivizumab and controlled with live RSV virus intranasal immunization and, formalin inactivated RSV vaccine. Active immunization with RSV F nanoparticle vaccine containing an alum adjuvant induced serum levels of palivizumab competing antibody (PCA) greater than passive administration of 15 mg/kg palivizumab (human prophylactic dose) in cotton rats and neutralized RSV-A and RSV-B viruses. Immunization prevented detectable RSV replication in the lungs and, unlike passive administration of palivizumab, in the nasal passage of challenged cotton rats. Histology of lung tissues following RSV challenge showed no enhanced disease in the vaccinated groups in contrast to formalin inactivated 'Lot 100' vaccine. Passive intramuscular administration of RSV F vaccine-induced immune sera one day prior to challenge of cotton rats reduced viral titers by 2 or more log10 virus per gram of lung and nasal tissue and at doses less than palivizumab. A recombinant RSV F nanoparticle vaccine protected lower and upper respiratory tract against both RSV A and B strain infection and induced polyclonal palivizumab competing antibodies similar to but potentially more broadly protective against RSV than palivizumab.
Assuntos
Nanopartículas , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Proteínas Virais de Fusão/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Antivirais/sangue , Feminino , Imunização Passiva , Pulmão/patologia , Pulmão/virologia , Testes de Neutralização , Palivizumab , Proteínas Recombinantes/imunologia , Vírus Sinciciais Respiratórios , Células Sf9 , Sigmodontinae , Vacinação , Vacinas de Produtos Inativados/imunologia , Carga ViralRESUMO
Respiratory Syncytial Virus (RSV) is a common virus that infects children and adults; however, children younger than two years of age tend to develop more serious respiratory symptoms. RSV is responsible for thousands of outpatient visits (e.g., emergency room/primary care physician), hospitalizations and can result in death. Treatment is primarily supportive care and the illness resolves without complications in most children. RSV prophylaxis with palivizumab is an option for high-risk infants and children, which can decrease hospitalization and length of stay. Immunocompromised patients are a special population of which ribavirin and palivizumab may be used for treatment. Currently, no medication or vaccine available has been able to show a reduction in mortality from RSV. Future vaccines are in the developmental stage and will hopefully decrease the symptomatic and economic burden of this disease.