Assuntos
Asma/imunologia , Linfócitos B/metabolismo , Imunoglobulina E/metabolismo , Proteínas de Membrana/metabolismo , Pólipos Nasais/imunologia , Seios Paranasais/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Rinite/imunologia , Sinusite/imunologia , Doença Crônica , Progressão da Doença , Humanos , Switching de Imunoglobulina , Imunoglobulina E/genética , Proteínas de Membrana/genética , Reação em Cadeia da Polimerase , Domínios Proteicos/genética , Domínios Proteicos/imunologia , Receptores de Antígenos de Linfócitos B/genéticaAssuntos
Alérgenos , Asma/sangue , Linfócitos B/citologia , Tonsila Palatina/citologia , Escarro/citologia , Asma/imunologia , Asma/fisiopatologia , Linfócitos B/imunologia , Medula Óssea , Células da Medula Óssea , Testes de Provocação Brônquica , Broncoconstritores , Volume Expiratório Forçado , Humanos , Imunoglobulina E/imunologia , Contagem de Linfócitos , Cloreto de MetacolinaRESUMO
In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.
RESUMO
Human bispecific antibodies have great potential for the treatment of human diseases. Although human IgG1 bispecific antibodies have been generated, few attempts have been reported in the scientific literature that extend bispecific antibodies to other human antibody isotypes. In this paper, we report our work expanding the knobs-into-holes bispecific antibody technology to the human IgG4 isotype. We apply this approach to generate a bispecific antibody that targets IL-4 and IL-13, two cytokines that play roles in type 2 inflammation. We show that IgG4 bispecific antibodies can be generated in large quantities with equivalent efficiency and quality and have comparable pharmacokinetic properties and lung partitioning, compared with the IgG1 isotype. This work broadens the range of published therapeutic bispecific antibodies with natural surface architecture and provides additional options for the generation of bispecific antibodies with differing effector functions through the use of different antibody isotypes.
Assuntos
Anticorpos Biespecíficos/imunologia , Regulação da Expressão Gênica , Imunoglobulina G/imunologia , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Animais , Anticorpos Biespecíficos/biossíntese , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Imunoglobulina G/biossíntese , Pulmão/imunologia , Pulmão/metabolismo , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Plasmídeos/metabolismo , Engenharia de Proteínas/métodos , Ressonância de Plasmônio de SuperfícieRESUMO
Asthma is a chronic respiratory disorder canonically associated with type 2 airway inflammation as characterized by elevated levels of eosinophils, immunoglobulin E, and cytokines including interleukin (IL) 4, IL5, IL9, and IL13 and tumor necrosis factor (TNF) α. However, mounting evidence has shown that considerable heterogeneity exists in human asthma in terms of the nature and intensity of airway inflammation. While many asthma patients achieve acceptable control of symptoms with standard-of-care therapies such as ß2-adrenergic agonists and inhaled corticosteroids, a minority remains symptomatic despite maximal standard-of-care therapy and constitutes a significant unmet medical need. A growing number of investigational therapeutics under clinical development for asthma are biologic therapies that specifically target mediators of type 2 airway inflammation. In this chapter, we consider the biological functions of therapeutic targets in asthma and data from clinical trials of biologic agents directed against these targets. We discuss recent clinical trial results in terms of four key components of drug development: target selection, molecule selection, outcome selection, and patient selection, with particular attention paid to the emerging role of biomarkers in clinical development for asthma.
Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Terapia de Alvo Molecular , Animais , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacocinética , Antiasmáticos/farmacologia , Asma/imunologia , Asma/metabolismo , Produtos Biológicos/efeitos adversos , Produtos Biológicos/farmacocinética , Produtos Biológicos/farmacologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Pesquisa Biomédica/tendências , Humanos , Farmacologia Clínica/tendências , Projetos de Pesquisa/tendênciasAssuntos
Antirreumáticos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Tirosina Quinase da Agamaglobulinemia , Sequência de Aminoácidos , Animais , Antirreumáticos/química , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/enzimologia , Sítios de Ligação , Modelos Animais de Doenças , Dados de Sequência Molecular , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo , Roedores , Relação Estrutura-AtividadeRESUMO
Uncontrolled mucosal immunity in the gastrointestinal tract of humans results in chronic inflammatory bowel disease (IBD), such as Crohn disease and ulcerative colitis. In early clinical trials as well as in animal models, IL-12 has been implicated as a major mediator of these diseases based on the ability of anti-p40 mAb treatment to reverse intestinal inflammation. The cytokine IL-23 shares the same p40 subunit with IL-12, and the anti-p40 mAbs used in human and mouse IBD studies neutralized the activities of both IL-12 and IL-23. IL-10-deficient mice spontaneously develop enterocolitis. To determine how IL-23 contributes to intestinal inflammation, we studied the disease susceptibility in the absence of either IL-23 or IL-12 in this model, as well as the ability of recombinant IL-23 to exacerbate IBD induced by T cell transfer. Our study shows that in these models, IL-23 is essential for manifestation of chronic intestinal inflammation, whereas IL-12 is not. A critical target of IL-23 is a unique subset of tissue-homing memory T cells, which are specifically activated by IL-23 to produce the proinflammatory mediators IL-17 and IL-6. This pathway may be responsible for chronic intestinal inflammation as well as other chronic autoimmune inflammatory diseases.
Assuntos
Colite/patologia , Inflamação/patologia , Interleucina-17/fisiologia , Interleucina-6/fisiologia , Interleucinas/fisiologia , Linfócitos T/patologia , Animais , Doenças Autoimunes/patologia , Humanos , Interleucina-23 , Subunidade p19 da Interleucina-23 , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/metabolismoRESUMO
OBJECTIVE AND BACKGROUND: Interleukin-10 (IL-10) is an anti-inflammatory cytokine regulating immune responses. We have previously reported that IL-10(-/-) mice experience accelerated alveolar bone loss. The purpose of the present study was to examine the timing of the manifestation of accelerated alveolar bone loss in IL-10(-/-) mice. MATERIALS AND METHODS: Twenty-four IL-10(-/-) and 21 IL-10(+/+) age-matched male 129/SvEv mice were used. Sacrifice times occurred at 1, 3 and 9.5 months of age. Alveolar bone loss was determined morphometrically on defleshed jaws. Enzyme-linked immunosorbent assay (ELISA) was used for determination of serum concentration of type I collagen C-telopeptide, a systemic marker of bone resorption. RESULTS: Alveolar bone loss for the entire IL-10(-/-) group was significantly different than for the IL-10(+/+) group (p = 0.025). There was no significant difference in alveolar bone loss between IL-10(-/-) and IL-10(+/+) mice at 1 and 3 months of age. At 9.5 months of age, IL-10(-/-) mice exhibited 39% greater alveolar bone loss than IL-10(+/+) mice (p = 0.018). For IL-10(-/-) mice, alveolar bone loss significantly increased with age. Serum C-telopeptide levels significantly decreased with age in both groups. IL-10(-/-) mice had consistently higher C-telopeptide levels than IL-10(+/+) mice and the difference between the two groups reached statistical significance (p = 0.011) for the 9.5-month-old mice. CONCLUSIONS: These results suggest that the accelerated alveolar bone loss observed in IL-10(-/-) mice is a late-onset condition and that lack of IL-10 may have an effect on bone homeostasis.
Assuntos
Perda do Osso Alveolar/metabolismo , Interleucina-10/fisiologia , Fatores Etários , Perda do Osso Alveolar/genética , Animais , Colágeno/sangue , Colágeno Tipo I , Modelos Animais de Doenças , Interleucina-10/genética , Masculino , Camundongos , Camundongos Knockout , Peptídeos/sangue , Estatísticas não ParamétricasRESUMO
The objective of this study was to define the relationship among Kupffer cells, O(2)(-) production, and TNF-alpha expression in the pathophysiology of postischemic liver injury following short and long periods of ischemia. Using different forms of superoxide dismutase with varying circulating half-lives, a monoclonal antibody directed against mouse TNF-alpha, and NADPH oxidase-deficient mice, we found that 45 or 90 min of partial (70%) liver ischemia and 6 h of reperfusion (I/R) produced time-dependent increases in liver injury and TNF-alpha expression in the absence of neutrophil infiltration. Furthermore, we observed that hepatocellular injury induced by short periods of ischemia were not dependent on formation of TNF-alpha but were dependent on Kupffer cells and NADPH oxidase-independent production of O(2)(-). However, liver injury induced by extended periods of ischemia appeared to require the presence of Kupffer cells, NADPH oxidase-derived O(2)(-), and TNF-alpha expression. We conclude that the sources for O(2)(-) formation and the relative importance of TNF-alpha in the pathophysiology of I/R-induced hepatocellular injury differ depending on the duration of ischemia.