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1.
Nat Commun ; 14(1): 7062, 2023 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-37923717

RESUMO

Passively administered monoclonal antibodies (mAbs) given before or after viral infection can prevent or blunt disease. Here, we examine the efficacy of aerosol mAb delivery to prevent infection and disease in rhesus macaques inoculated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant via intranasal and intratracheal routes. SARS-CoV-2 human mAbs or a human mAb directed to respiratory syncytial virus (RSV) are nebulized and delivered using positive airflow via facemask to sedated macaques pre- and post-infection. Nebulized human mAbs are detectable in nasal, oropharyngeal, and bronchoalveolar lavage (BAL) samples. SARS-CoV-2 mAb treatment significantly reduces levels of SARS-CoV-2 viral RNA and infectious virus in the upper and lower respiratory tracts relative to controls. Reductions in lung and BAL virus levels correspond to reduced BAL inflammatory cytokines and lung pathology. Aerosolized antibody therapy for SARS-CoV-2 could be effective for reducing viral burden and limiting disease severity.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Humanos , Macaca mulatta , COVID-19/patologia , Aerossóis e Gotículas Respiratórios , Pulmão/patologia , Anticorpos Antivirais , Replicação Viral , Anticorpos Monoclonais
2.
Cell Rep Med ; 2(3): 100218, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33649747

RESUMO

SARS-CoV-2 infection results in viral burden in the respiratory tract, enabling transmission and leading to substantial lung pathology. The 1212C2 fully human monoclonal antibody was derived from an IgM memory B cell of a COVID-19 patient, has high affinity for the Spike protein receptor binding domain, neutralizes SARS-CoV-2, and exhibits in vivo prophylactic and therapeutic activity in hamsters when delivered intraperitoneally, reducing upper and lower respiratory viral burden and lung pathology. Inhalation of nebulized 1212C2 at levels as low as 0.6 mg/kg, corresponding to 0.03 mg/kg lung-deposited dose, reduced the viral burden below the detection limit and mitigated lung pathology. The therapeutic efficacy of an exceedingly low dose of inhaled 1212C2 supports the rationale for local lung delivery for dose-sparing benefits, as compared to the conventional parenteral route of administration. These results suggest that the clinical development of 1212C2 formulated and delivered via inhalation for the treatment of SARS-CoV-2 infection should be considered.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Administração por Inalação , Animais , Anticorpos Monoclonais/classificação , Anticorpos Monoclonais/imunologia , COVID-19/virologia , Cricetinae , Modelos Animais de Doenças , Mapeamento de Epitopos , Epitopos/imunologia , Feminino , Humanos , Imunoglobulina M/imunologia , Masculino , Células B de Memória/citologia , Células B de Memória/metabolismo , Pessoa de Meia-Idade , Testes de Neutralização , Filogenia , Domínios Proteicos/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo
3.
Pharm Res ; 33(5): 1144-60, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26818839

RESUMO

PURPOSE: The goal of this research is to develop stable formulations for live attenuated influenza vaccines (LAIV) by employing the drying methods freeze drying, spray drying, and foam drying. METHODS: Formulated live attenuated Type-A H1N1 and B-strain influenza vaccines with a variety of excipient combinations were dried using one of the three drying methods. Process and storage stability at 4, 25 and 37°C of the LAIV in these formulations was monitored using a TCID50 potency assay. Their immunogenicity was also evaluated in a ferret model. RESULTS: The thermal stability of H1N1 vaccine was significantly enhanced through application of unique formulation combinations and drying processes. Foam dried formulations were as much as an order of magnitude more stable than either spray dried or freeze dried formulations, while exhibiting low process loss and full retention of immunogenicity. Based on long-term stability data, foam dried formulations exhibited a shelf life at 4, 25 and 37°C of >2, 1.5 years and 4.5 months, respectively. Foam dried LAIV Type-B manufactured using the same formulation and process parameters as H1N1 were imparted with a similar level of stability. CONCLUSION: Foam drying processing methods with appropriate selection of formulation components can produce an order of magnitude improvement in LAIV stability over other drying methods.


Assuntos
Betainfluenzavirus/imunologia , Dessecação/métodos , Liofilização/métodos , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/química , Infecções por Orthomyxoviridae/prevenção & controle , Vacinas Atenuadas/química , Animais , Linhagem Celular , Cães , Estabilidade de Medicamentos , Excipientes/química , Feminino , Furões , Humanos , Vírus da Influenza A Subtipo H1N1/química , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/farmacologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Betainfluenzavirus/química , Infecções por Orthomyxoviridae/imunologia , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/farmacologia
4.
Adv Drug Deliv Rev ; 93: 95-108, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26277263

RESUMO

Delivery of proteins to mucosal tissues of GI tract typically utilize formulations which protect against proteolysis and target the mucosal tissues. Using case studies from literature and the authors' own work, the in-process stability and solid state storage stability of biopharmaceuticals formulated in delivery systems designed for oral delivery to the GI tract will be reviewed. Among the range of delivery systems, biodegradable polymer systems for protection and controlled release of proteins have been the most studied; hence these systems will be covered in greater depth. These delivery systems include polymeric biodegradable microspheres or nanospheres that contain proteins or vaccines, which are designed to reduce the number of administrations/inoculations and the total protein dose required to achieve the desired biological effect. Specifically, this review will include a landscape survey of the systems that have been studied, the manufacturing processes involved, stability through the manufacturing process, key pharmaceutical formulation parameters that impact stability of the encased proteins, and storage stability of the encapsulated proteins in these delivery systems.


Assuntos
Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Proteínas/administração & dosagem , Administração Oral , Animais , Química Farmacêutica/métodos , Armazenamento de Medicamentos , Humanos , Microesferas , Nanosferas , Polímeros/química , Estabilidade Proteica , Proteínas/química
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