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2.
PLoS One ; 11(5): e0154616, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27171010

RESUMO

A proof-of-concept study evaluating the potential of Streptococcus pneumoniae Pneumococcal Surface Protein A (PspA) as a passive immunization target was conducted. We describe the generation and isolation of several broadly reactive mouse anti-PspA monoclonal antibodies (mAbs). MAb 140H1 displayed (i) 98% strain coverage, (ii) activity in complement deposition and opsonophagocytic killing (OPK) assays, which are thought to predict the in vivo efficacy of anti-pneumococcal mAbs, (iii) efficacy in mouse sepsis models both alone and in combination with standard-of-care antibiotics, and (iv) therapeutic activity in a mouse pneumonia model. Moreover, we demonstrate that antibody engineering can significantly enhance anti-PspA mAb effector function. We believe that PspA has promising potential as a target for the therapy of invasive pneumococcal disease by mAbs, which could be used alone or in conjunction with standard-of-care antibiotics.


Assuntos
Anticorpos Monoclonais/imunologia , Proteínas de Bactérias/imunologia , Streptococcus pneumoniae/imunologia , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Complemento C3/metabolismo , Modelos Animais de Doenças , Mapeamento de Epitopos , Feminino , Humanos , Imunoglobulina G/sangue , Pneumopatias/imunologia , Pneumopatias/microbiologia , Camundongos Endogâmicos BALB C , Proteínas Opsonizantes/metabolismo , Fagócitos/metabolismo , Fagocitose , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Ligação Proteica , Sepse/tratamento farmacológico , Sepse/imunologia , Sepse/microbiologia , Resultado do Tratamento
3.
Antiviral Res ; 111: 60-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25218949

RESUMO

Influenza virus is a global health concern due to its unpredictable pandemic potential. Frequent mutations of surface molecules, hemagglutinin (HA) and neuraminidase (NA), contribute to low efficacy of the annual flu vaccine and therapeutic resistance to standard antiviral agents. The populations at high risk of influenza virus infection, such as the elderly and infants, generally mount low immune responses to vaccines, and develop severe disease after infection. Novel therapeutics with high effectiveness and mutation resistance are needed. Previously, we described the generation of a fully human influenza virus matrix protein 2 (M2) specific monoclonal antibody (mAb), Z3G1, which recognized the majority of M2 variants from natural viral isolates, including highly pathogenic avian strains. Passive immunotherapy with Z3G1 significantly protected mice from the infection when administered either prophylactically or 1-2days post infection. In the present study, we showed that Z3G1 significantly protected mice from lethal infection when treatment was initiated 3days post infection. In addition, therapeutic administration of Z3G1 reduced lung viral titers in mice infected with different viral strains, including amantadine and oseltamivir-resistant strains. Furthermore, prophylactic and therapeutic administration of Z3G1 sustained O2 saturation and reduced lung pathology in monkeys infected with a pandemic H1N1 strain. Finally, de-fucosylated Z3G1 with an IgG1/IgG3 chimeric Fc region was generated (AccretaMab® Z3G1), and showed increased ADCC and CDC in vitro. Our data suggest that the anti-M2 mAb Z3G1 has great potential as a novel anti-flu therapeutic agent.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Imunização Passiva , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Influenza Humana/virologia , Macaca , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas da Matriz Viral/imunologia
4.
Antivir Ther ; 15(4): 661-75, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20587859

RESUMO

BACKGROUND: Treatment of rare severe side effects of vaccinia virus (VACV) immunization in humans is currently very challenging. VACV possesses two immunologically distinct virion forms in vivo - intracellular mature virion (MV, IMV) and extracellular virion (EV, EEV). METHODS: Antibody-mediated therapeutic efficacy was determined against VACV infection in a small animal model of progressive vaccinia. The model consisted of severe combined immunodeficiency mice infected with VACV New York City Board of Health vaccine strain and treated with monoclonal antibodies (mAbs). RESULTS: Here, we show that combination therapy with two fully human mAbs against an immunodominant MV antigen, H3 (H3L), and an EV antigen, B5 (B5R), provides significantly better protection against disease and death than either single human monoclonal or human vaccinia immune globulin, the currently licensed therapeutic for side effects of smallpox vaccination. CONCLUSIONS: The preclinical studies validate that this combination of mAbs against H3 and B5 is a promising approach as a poxvirus infection treatment for use in humans.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Proteínas de Transporte/imunologia , Vaccinia virus/imunologia , Vacínia/tratamento farmacológico , Proteínas do Envelope Viral/imunologia , Proteínas da Matriz Viral/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/uso terapêutico , Chlorocebus aethiops , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Testes de Neutralização , Resultado do Tratamento , Vacínia/imunologia , Células Vero
5.
J Virol ; 83(23): 12355-67, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19793826

RESUMO

Antibodies against the extracellular virion (EV or EEV) form of vaccinia virus are an important component of protective immunity in animal models and likely contribute to the protection of immunized humans against poxviruses. Using fully human monoclonal antibodies (MAbs), we now have shown that the protective attributes of the human anti-B5 antibody response to the smallpox vaccine (vaccinia virus) are heavily dependent on effector functions. By switching Fc domains of a single MAb, we have definitively shown that neutralization in vitro--and protection in vivo in a mouse model--by the human anti-B5 immunoglobulin G MAbs is isotype dependent, thereby demonstrating that efficient protection by these antibodies is not simply dependent on binding an appropriate vaccinia virion antigen with high affinity but in fact requires antibody effector function. The complement components C3 and C1q, but not C5, were required for neutralization. We also have demonstrated that human MAbs against B5 can potently direct complement-dependent cytotoxicity of vaccinia virus-infected cells. Each of these results was then extended to the polyclonal human antibody response to the smallpox vaccine. A model is proposed to explain the mechanism of EV neutralization. Altogether these findings enhance our understanding of the central protective activities of smallpox vaccine-elicited antibodies in immunized humans.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Isotipos de Imunoglobulinas/imunologia , Varíola/prevenção & controle , Vaccinia virus/imunologia , Proteínas da Matriz Viral/imunologia , Animais , Peso Corporal , Complemento C1q/imunologia , Complemento C3/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Biológicos , Testes de Neutralização , Análise de Sobrevida
6.
J Virol ; 83(3): 1201-15, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19019965

RESUMO

Antibody neutralization is an important component of protective immunity against vaccinia virus (VACV). Two distinct virion forms, mature virion and enveloped virion (MV and EV, respectively), possess separate functions and nonoverlapping immunological properties. In this study we examined the mechanics of EV neutralization, focusing on EV protein B5 (also called B5R). We show that neutralization of EV is predominantly complement dependent. From a panel of high-affinity anti-B5 monoclonal antibodies (MAbs), the only potent neutralizer in vitro (90% at 535 ng/ml) was an immunoglobulin G2a (IgG2a), and neutralization was complement mediated. This MAb was the most protective in vivo against lethal intranasal VACV challenge. Further studies demonstrated that in vivo depletion of complement caused a >50% loss of anti-B5 IgG2a protection, directly establishing the importance of complement for protection against the EV form. However, the mechanism of protection is not sterilizing immunity via elimination of the inoculum as the viral inoculum consisted of a purified MV form. The prevention of illness in vivo indicated rapid control of infection. We further demonstrate that antibody-mediated killing of VACV-infected cells expressing surface B5 is a second protective mechanism provided by complement-fixing anti-B5 IgG. Cell killing was very efficient, and this effector function was highly isotype specific. These results indicate that anti-B5 antibody-directed cell lysis via complement is a powerful mechanism for clearance of infected cells, keeping poxvirus-infected cells from being invisible to humoral immune responses. These findings highlight the importance of multiple mechanisms of antibody-mediated protection against VACV and point to key immunobiological differences between MVs and EVs that impact the outcome of infection.


Assuntos
Proteínas do Sistema Complemento/fisiologia , Vaccinia virus/imunologia , Vírion/imunologia , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Chlorocebus aethiops , Ensaio de Imunoadsorção Enzimática , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Neutralização , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Células Vero
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