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1.
Sci Transl Med ; 9(384)2017 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-28381540

RESUMO

As observed during the 2013-2016 Ebola virus disease epidemic, containment of filovirus outbreaks is challenging and made more difficult by the lack of approved vaccine or therapeutic options. Marburg and Ravn viruses are highly virulent and cause severe and frequently lethal disease in humans. Monoclonal antibodies (mAbs) are a platform technology in wide use for autoimmune and oncology indications. Previously, we described human mAbs that can protect mice from lethal challenge with Marburg virus. We demonstrate that one of these mAbs, MR191-N, can confer a survival benefit of up to 100% to Marburg or Ravn virus-infected rhesus macaques when treatment is initiated up to 5 days post-inoculation. These findings extend the small but growing body of evidence that mAbs can impart therapeutic benefit during advanced stages of disease with highly virulent viruses and could be useful in epidemic settings.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Infecções por Filoviridae/tratamento farmacológico , Filoviridae/fisiologia , Doença do Vírus de Marburg/tratamento farmacológico , Marburgvirus/fisiologia , Animais , Proteção Cruzada , Infecções por Filoviridae/virologia , Cobaias , Humanos , Macaca fascicularis , Macaca mulatta , Doença do Vírus de Marburg/virologia , Projetos Piloto
2.
Proc Natl Acad Sci U S A ; 113(16): 4458-63, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-27044104

RESUMO

Countermeasures against potential biothreat agents remain important to US Homeland Security, and many of these pharmaceuticals could have dual use in the improvement of global public health. Junin virus, the causative agent of Argentine hemorrhagic fever (AHF), is an arenavirus identified as a category A high-priority agent. There are no Food and Drug Administration (FDA) approved drugs available for preventing or treating AHF, and the current treatment option is limited to administration of immune plasma. Whereas immune plasma demonstrates the feasibility of passive immunotherapy, it is limited in quantity, variable in quality, and poses safety risks such as transmission of transfusion-borne diseases. In an effort to develop a monoclonal antibody (mAb)-based alternative to plasma, three previously described neutralizing murine mAbs were expressed as mouse-human chimeric antibodies and evaluated in the guinea pig model of AHF. These mAbs provided 100% protection against lethal challenge when administered 2 d after infection (dpi), and one of them (J199) was capable of providing 100% protection when treatment was initiated 6 dpi and 92% protection when initiated 7 dpi. The efficacy of J199 is superior to that previously described for all other evaluated drugs, and its high potency suggests that mAbs like J199 offer an economical alternative to immune plasma and an effective dual use (bioterrorism/public health) therapeutic.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Antivirais/farmacologia , Febre Hemorrágica Americana/tratamento farmacológico , Febre Hemorrágica Americana/imunologia , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Cobaias , Humanos , Vírus Junin , Camundongos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/farmacologia
3.
PLoS One ; 10(6): e0129618, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26086915

RESUMO

In Alzheimer's disease (AD), one of the early responses to Aß amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aß-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1ΔE9 mice were used in small animal PET with a CB2-targeting radiotracer, [11C]A836339. These studies revealed increased binding of [11C]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with Aß plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that Aß amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.


Assuntos
Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/análise , Amiloidose/patologia , Inflamação/patologia , Neurônios/patologia , Receptor CB2 de Canabinoide/análise , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/imunologia , Precursor de Proteína beta-Amiloide/imunologia , Amiloidose/diagnóstico por imagem , Amiloidose/imunologia , Animais , Biomarcadores/análise , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/diagnóstico por imagem , Microglia/imunologia , Microglia/patologia , Neurônios/diagnóstico por imagem , Neurônios/imunologia , Tomografia por Emissão de Pósitrons , Receptor CB2 de Canabinoide/imunologia
4.
Hum Antibodies ; 23(3-4): 49-56, 2015 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-27472862

RESUMO

This review describes the history of Ebola monoclonal antibody (mAb) development leading up to the recent severe Ebola outbreak in West Africa. The Ebola virus has presented numerous perplexing challenges in the long effort to develop therapeutic antibody strategies. Since the first report of a neutralizing human anti-Ebola mAb in 1999, the straightforward progression from in vitro neutralization resulting in in vivo protection and therapy has not occurred. A number of mAbs, including the first reported, failed to protect non-human primates (NHPs) in spite of protection in rodents. An appreciation of the role of effector functions to antibody efficacy has contributed significantly to understanding mechanisms of in vivo protection. However a crucial contribution, as measured by post-exposure therapy of NHPs, involved the comprehensive testing of mAb cocktails. This effort was aided by the use of plant production technology where various combinations of mAbs could be rapidly produced and tested. Introduction of appropriate modifications, such as specific glycan profiles, also improved therapeutic efficacy. The resulting cocktail, ZMapp™, consists of three mAbs that were identified from numerous mAb candidates. ZMapp™ \ is now being evaluated in human clinical trials but has already played a role in bringing awareness to the potential of antibody therapy for Ebola.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Doença pelo Vírus Ebola/terapia , Imunização Passiva/métodos , Imunoglobulina G/uso terapêutico , África Ocidental , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Antivirais/biossíntese , Ebolavirus/efeitos dos fármacos , Ebolavirus/imunologia , Ebolavirus/patogenicidade , Epitopos/química , Glicosilação , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/mortalidade , Doença pelo Vírus Ebola/virologia , Humanos , Imunoglobulina G/biossíntese , Macaca mulatta , Camundongos , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Engenharia de Proteínas , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/uso terapêutico , Análise de Sobrevida
6.
Proc Natl Acad Sci U S A ; 111(16): 5992-7, 2014 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-24711420

RESUMO

Respiratory syncytial virus (RSV) can cause devastating lower respiratory tract infections in preterm infants or when other serious health problems are present. Immunoprophylaxis with palivizumab (Synagis), a humanized IgG1 mAb, is the current standard of care for preventing RSV infection in at-risk neonates. We have explored the contribution of effector function to palivizumab efficacy using a plant-based expression system to produce palivizumab N-glycan structure variants with high homogeneity on different antibody isotypes. We compared these isotype and N-glycoform variants with commercially available palivizumab with respect to both in vitro receptor and C1q binding and in vivo efficacy. Whereas the affinity for antigen and neutralization activity of each variant were indistinguishable from those of palivizumab, their Fcγ receptor binding profiles were very different, which was reflected in either a reduced or enhanced ability to influence the RSV lung titer in challenged cotton rats. Enhanced Fcγ receptor binding was associated with reduced viral lung titers compared with palivizumab, whereas abrogation of receptor binding led to a drastic reduction in efficacy. The results support the hypotheses that classic antibody neutralization is a minor component of efficacy by palivizumab in the cotton rat and that antibody-dependent cell-mediated cytotoxicity activity can significantly enhance the efficacy of this antiviral mAb.


Assuntos
Anticorpos Antivirais/química , Anticorpos Antivirais/uso terapêutico , Polissacarídeos/metabolismo , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Sigmodontinae/virologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/farmacologia , Complemento C1q/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Masculino , Testes de Neutralização , Ligação Proteica/efeitos dos fármacos , Receptores Fc/metabolismo , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Sigmodontinae/imunologia , Resultado do Tratamento
7.
Curr Top Microbiol Immunol ; 375: 107-26, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-22772797

RESUMO

Antibody-based products are not widely available to address many global health challenges due to high costs, limited manufacturing capacity, and long manufacturing lead times. There are now tremendous opportunities to address these industrialization challenges as a result of revolutionary advances in plant virus-based transient expression. This review focuses on some antibody-based products that are in preclinical and clinical development, and have scaled up manufacturing and purification (mg of purified mAb/kg of biomass). Plant virus-based antibody products provide lower upfront cost, shorter time to clinical and market supply, and lower cost of goods (COGs). Further, some plant virus-based mAbs may provide improvements in pharmacokinetics, safety and efficacy.


Assuntos
Anticorpos Monoclonais/genética , Vírus de Plantas/genética , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/uso terapêutico , Vacinas contra Ebola/uso terapêutico , Humanos , Idiótipos de Imunoglobulinas/uso terapêutico
8.
Microbiol Spectr ; 2(1): AID-0004-2012, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26082108

RESUMO

Numerous monoclonal antibodies (MAbs) that recognize and neutralize infectious pathogens have been isolated and developed over the years. The fact that infectious diseases can involve large populations of infected individuals is an important factor that has motivated the search for both cost-effective and scalable methods of antibody production. The current technologies for production of antibodies in plants allow for very rapid expression and evaluation that can also be readily scaled for multikilogram production runs. In addition, recent progress in manipulating glycosylation in plant production systems has allowed for the evaluation of antibodies containing glycans that are nearly homogeneous, are mammalian in structure, and have enhanced neutralizing capabilities. Among the anti-infectious disease antibodies that have been produced in plants are included those intended for prevention or treatment of anthrax, Clostridium perfringens, Ebola virus, human immunodeficiency virus, herpes simplex virus, rabies, respiratory syncytial virus, staphylococcal enterotoxin, West Nile virus, and tooth decay. Animal and human efficacy data for these MAbs are discussed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Controle de Doenças Transmissíveis/métodos , Doenças Transmissíveis/terapia , Plantas Geneticamente Modificadas/metabolismo , Proteínas Recombinantes/uso terapêutico , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/metabolismo , Humanos , Imunoterapia/métodos , Plantas Geneticamente Modificadas/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
9.
Clin Dev Immunol ; 2013: 632893, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23840243

RESUMO

Vaccination strategies depend entirely on the appropriate responsiveness of our immune system against particular antigens. For this active immunization to be truly effective, neutralizing antibodies (nAbs) need to efficiently counter the infectivity or propagation of the pathogen. Some viruses, including HIV, are able to take advantage of this immune response in order to evade nAbs. This review focuses on viral immune evasion strategies that result directly from a robust immune response to infection or vaccination. A rationale for multi-Ab therapy to circumvent this phenomenon is discussed. Progress in the formulation, production, and regulatory approval of monoclonal antibodies (mAbs) is presented.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Antivirais/farmacologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Anticorpos Monoclonais/biossíntese , Anticorpos Neutralizantes/biossíntese , Antígenos Virais/imunologia , Antivirais/metabolismo , Aprovação de Drogas , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Evasão da Resposta Imune , Replicação Viral/imunologia
10.
MAbs ; 5(2): 263-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23396091

RESUMO

Severe lower respiratory tract infection in infants and small children is commonly caused by respiratory syncytial virus (RSV). Palivizumab (Synagis(®)), a humanized IgG1 monoclonal antibody (mAb) approved for RSV immunoprophylaxis in at-risk neonates, is highly effective, but pharmacoeconomic analyses suggest its use may not be cost-effective. Previously described potent RSV neutralizers (human Fab R19 and F2-5; human IgG RF-1 and RF-2) were produced in IgG format in a rapid and inexpensive Nicotiana-based manufacturing system for comparison with palivizumab. Both plant-derived (palivizumab-N) and commercial palivizumab, which is produced in a mouse myeloma cell line, showed protection in prophylactic (p < 0.001 for both mAbs) and therapeutic protocols (p < 0.001 and p < 0.05 respectively). The additional plant-derived human mAbs directed against alternative epitopes displayed neutralizing activity, but conferred less protection in vivo than palivizumab-N or palivizumab. Palivizumab remains one of the most efficacious RSV mAbs described to date. Production in plants may reduce manufacturing costs and improve the pharmacoeconomics of RSV immunoprophylaxis and therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Nicotiana/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Animais , Anticorpos Monoclonais Humanizados/economia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Neutralizantes/economia , Anticorpos Neutralizantes/imunologia , Modelos Animais de Doenças , Humanos , Palivizumab , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/virologia , Sigmodontinae , Resultado do Tratamento
11.
Neuropsychopharmacology ; 37(1): 261-77, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21937983

RESUMO

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation-from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aß immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Pesquisa Translacional Biomédica/tendências , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Humanos
12.
Proc Natl Acad Sci U S A ; 108(51): 20690-4, 2011 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-22143789

RESUMO

No countermeasures currently exist for the prevention or treatment of the severe sequelae of Filovirus (such as Ebola virus; EBOV) infection. To overcome this limitation in our biodefense preparedness, we have designed monoclonal antibodies (mAbs) which could be used in humans as immunoprotectants for EBOV, starting with a murine mAb (13F6) that recognizes the heavily glycosylated mucin-like domain of the virion-attached glycoprotein (GP). Point mutations were introduced into the variable region of the murine mAb to remove predicted human T-cell epitopes, and the variable regions joined to human constant regions to generate a mAb (h-13F6) appropriate for development for human use. We have evaluated the efficacy of three variants of h-13F6 carrying different glycosylation patterns in a lethal mouse EBOV challenge model. The pattern of glycosylation of the various mAbs was found to correlate to level of protection, with aglycosylated h-13F6 providing the least potent efficacy (ED(50) = 33 µg). A version with typical heterogenous mammalian glycoforms (ED(50) = 11 µg) had similar potency to the original murine mAb. However, h-13F6 carrying complex N-glycosylation lacking core fucose exhibited superior potency (ED(50) = 3 µg). Binding studies using Fcγ receptors revealed enhanced binding of nonfucosylated h-13F6 to mouse and human FcγRIII. Together the results indicate the presence of Fc N-glycans enhances the protective efficacy of h-13F6, and that mAbs manufactured with uniform glycosylation and a higher potency glycoform offer promise as biodefense therapeutics.


Assuntos
Ebolavirus/metabolismo , Fucose/imunologia , Animais , Anticorpos Monoclonais/química , Antivirais/química , Complemento C1q/química , Ebolavirus/imunologia , Feminino , Fucose/química , Glicosilação , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Sistema Imunitário , Imunização Passiva , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Ressonância de Plasmônio de Superfície , Nicotiana
13.
Hum Vaccin ; 7(3): 349-56, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21358287

RESUMO

Antibody based products are not widely available to address multiple global health challenges due to high costs, limited manufacturing capacity, and long manufacturing lead times. Nicotiana-based manufacturing of antibody products may now begin to address these challenges as a result of revolutionary advances in transient expression and altered glycosylation pathways. This review provides examples of emerging antibody-based products (mucosal and systemic) that could be competitive and commercially viable when the attributes of Nicotiana-based manufacturing (large scale, versatile, rapid, low cost) are utilized.


Assuntos
Anticorpos Monoclonais/biossíntese , Formação de Anticorpos , Nicotiana/metabolismo , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Produtos Biológicos/biossíntese , Guerra Biológica/prevenção & controle , Comércio , Doenças Transmissíveis Emergentes/imunologia , Doenças Transmissíveis Emergentes/prevenção & controle , Anticoncepção/métodos , Glicosilação , Humanos , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Inflamação/tratamento farmacológico , Camundongos , Polissacarídeos/biossíntese , Gravidez não Planejada , Infecções por Vírus Respiratório Sincicial/economia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sinciciais Respiratórios/imunologia , Infecções Sexualmente Transmissíveis/prevenção & controle , Nicotiana/imunologia , Vacinas de Subunidades Antigênicas/biossíntese
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