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1.
Cancer Immunol Res ; 8(12): 1568-1582, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32999002

RESUMEN

The immunosuppressive tumor microenvironment constitutes a significant hurdle to immune checkpoint inhibitor responses. Both soluble factors and specialized immune cells, such as regulatory T cells (Treg), are key components of active intratumoral immunosuppression. Inducible costimulatory receptor (ICOS) can be highly expressed in the tumor microenvironment, especially on immunosuppressive Treg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we performed immune profiling of samples from tumor-bearing mice and patients with cancer to demonstrate differential expression of ICOS in immune T-cell subsets in different tissues. ICOS expression was higher on intratumoral Treg than on effector CD8 T cells. In addition, by immunizing an Icos knockout transgenic mouse line expressing antibodies with human variable domains, we selected a fully human IgG1 antibody called KY1044 that bound ICOS from different species. We showed that KY1044 induced sustained depletion of ICOShigh T cells but was also associated with increased secretion of proinflammatory cytokines from ICOSlow effector T cells (Teff). In syngeneic mouse tumor models, KY1044 depleted ICOShigh Treg and increased the intratumoral TEff:Treg ratio, resulting in increased secretion of IFNγ and TNFα by TEff cells. KY1044 demonstrated monotherapy antitumor efficacy and improved anti-PD-L1 efficacy. In summary, we demonstrated that using KY1044, one can exploit the differential expression of ICOS on T-cell subtypes to improve the intratumoral immune contexture and restore an antitumor immune response.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/efectos de los fármacos , Animales , Anticuerpos Monoclonales/inmunología , Antígeno B7-H1/inmunología , Línea Celular Tumoral , Citocinas/metabolismo , Femenino , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
2.
Nat Commun ; 10(1): 5183, 2019 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-31729368

RESUMEN

Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.


Asunto(s)
Anticuerpos/administración & dosificación , Hipertensión Pulmonar Primaria Familiar/tratamiento farmacológico , Osteoprotegerina/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Hipertensión Pulmonar Primaria Familiar/genética , Hipertensión Pulmonar Primaria Familiar/metabolismo , Hipertensión Pulmonar Primaria Familiar/fisiopatología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Osteoprotegerina/genética , Unión Proteica , Arteria Pulmonar/citología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Ratas , Ratas Wistar , Remodelación Vascular/efectos de los fármacos
3.
Cancer Immunol Res ; 5(1): 29-41, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27923825

RESUMEN

Murine syngeneic tumor models are critical to novel immuno-based therapy development, but the molecular and immunologic features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We used array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell-specific genes that suggested differences in tumor immune infiltrates between models. Further investigation using flow cytometry showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor "inflamed" and "non-inflamed" tumor immune infiltrate phenotypes. We also found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell-rich tumor immune infiltrate has been correlated with increased efficacy of immunotherapies in the clinic, and these differences could underlie the varying response profiles to immunotherapy between the syngeneic models. This characterization highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo Cancer Immunol Res; 5(1); 29-41. ©2016 AACR.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Exoma , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Inmunomodulación/efectos de los fármacos , Inmunomodulación/genética , Ratones , Terapia Molecular Dirigida , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Transcriptoma , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología
4.
Cancer Immunol Res ; 3(9): 1052-62, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25943534

RESUMEN

Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.


Asunto(s)
Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/administración & dosificación , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-1/metabolismo , Antígeno B7-H1/metabolismo , Unión Competitiva , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Humanos , Activación de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Melanoma/inmunología , Melanoma/patología , Melanoma/prevención & control , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/prevención & control , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Eur J Immunol ; 44(1): 162-72, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24114634

RESUMEN

CD40 agonists are showing activity in early clinical trials in patients with advanced cancer. In animal models, CD40 agonists synergise with T-cell-activating therapies to inhibit tumour growth by driving tumour macrophage repolarisation from an immunosuppressive to a Th1 immunostimulatory, tumouricidal phenotype. We therefore tested the hypothesis that T-cell-derived cytokines license anti-tumour functions in CD40-activated human macrophages. CD40 ligand (CD40L) alone activated macrophages to produce immunosuppressive IL-10, in a similar fashion to bacterial LPS, but failed to promote anti-tumour functions. The Th1 cytokine IFN-γ optimally licensed CD40L-induced macrophage anti-tumour functions, inducing a switch from IL-10 to IL-12p70 production, promoting macrophage-mediated Th1 T-cell skewing and enhancing tumouricidal activity. We found that even the Th2 cytokines IL-4 and IL-13 promoted IL-12p70 production (albeit without inhibiting IL-10 production) and enhanced Th1 T-cell skewing by CD40L-activated macrophages. However, IL-4 and IL-13 did not enhance tumouricidal activity in CD40L-activated macrophages. Thus, while both Th1 and Th2 cytokines biased macrophages to a Th1 immunostimulatory phenotype, only Th1 cytokines promoted tumouricidal activity in CD40L-activated macrophages. The presence of tumour-infiltrating Th1 or Th2 cells might therefore be predictive for patient response to CD40 agonism.


Asunto(s)
Citocinas/metabolismo , Inmunoterapia Adoptiva/métodos , Macrófagos/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Células TH1/inmunología , Células Th2/inmunología , Animales , Antígenos de Neoplasias/inmunología , Antígenos CD40/inmunología , Ligando de CD40/inmunología , Células Cultivadas , Citocinas/inmunología , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Humanos , Inmunidad Celular , Activación de Macrófagos , Balance Th1 - Th2
6.
Protein Eng Des Sel ; 25(10): 631-8, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22942395

RESUMEN

Many natural human proteins have functional properties that make them useful as therapeutic drugs. However, not all these proteins are compatible with large-scale manufacturing processes or sufficiently stable to be stored for long periods prior to use. In this study, we focus on small four-helix bundle proteins and employ ribosome display in conjunction with three parallel selection pressures to favour the isolation of variant proteins with improved expression, solubility and stability. This in vitro evolution strategy was applied to two human proteins with known drug development issues, granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO). In the case of G-CSF, the soluble expression levels in Escherichia coli were improved 1000-fold, while for EPO the level of aggregation in an accelerated shelf-life study was reduced from over 80% to undetectable levels. These results exemplify the general utility of our in vitro evolution strategy for improving the drug-like properties of therapeutic proteins.


Asunto(s)
Evolución Molecular Dirigida/métodos , Eritropoyetina/genética , Factor Estimulante de Colonias de Granulocitos/genética , Animales , Eritropoyetina/química , Eritropoyetina/farmacocinética , Escherichia coli/genética , Factor Estimulante de Colonias de Granulocitos/química , Humanos , Ratones , Modelos Moleculares , Estabilidad Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacocinética , Ribosomas/genética , Solubilidad
7.
Proc Natl Acad Sci U S A ; 105(51): 20251-6, 2008 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-19073914

RESUMEN

TGF-beta isoforms are key modulators of a broad range of biological pathways and increasingly are exploited as therapeutic targets. Here, we describe the crystal structures of a pan-TGF-beta neutralizing antibody, GC-1008, alone and in complex with TGF-beta3. The antibody is currently in clinical evaluation for idiopathic pulmonary fibrosis, melanoma, and renal cell cancer. GC-1008 recognizes an asymmetric binding interface across the TGF-beta homodimer with high affinity. Whereas both cognate receptors, TGF-beta-receptor types I and II, are required to recognize all 3 TGF-beta isoforms, GC-1008 has been engineered to bind with high affinity to TGF-beta1, 2, and 3 via a single interaction surface. Comparison with existing structures and models of TGF-beta interaction with its receptors suggests that the antibody binds to a similar epitope to the 2 receptors together and is therefore a structurally different but functionally identical mimic of the binding mode of both receptors.


Asunto(s)
Anticuerpos/metabolismo , Citocinas/inmunología , Imitación Molecular , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Epítopos , Humanos , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta2/metabolismo , Factor de Crecimiento Transformador beta3/metabolismo
8.
Kidney Int ; 66(5): 1774-84, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15496148

RESUMEN

BACKGROUND: Although angiotensin II (Ang II) blockade is rapidly becoming standard antifibrotic therapy in renal diseases, current data suggest that Ang II blockade alone cannot stop fibrotic disease. New therapies, such as antibodies to transforming growth factor-beta (TGF-beta), or drug combinations will be required to further slow or halt disease progression. Here, using the anti-Thy1 model of glomerulonephritis, the maximally therapeutic dose of the TGF-beta neutralizing mouse monoclonal antibody (1D11) was determined and compared with the maximally effective dose of enalapril. Then, the effect of combining both treatments at maximal doses was determined. METHODS: After disease induction with the anti-Thy1 antibody, OX-7, increasing doses of 1D11 were given intraperitoneally (IP) on days 1, 3, and 5. Enalapril was administered in drinking water from day 1. The fibrotic response was assessed at day 6. RESULTS: 1D11 dose-dependently reduced fibrosis, with the 0.5 and 5 mg/kg doses showing maximal therapeutic effects, reducing period-acid Schiff (PAS) staining by 56% and 45%, respectively. Fibronectin and collagen I staining was reduced by 32% to 36%, respectively. Glomerular mRNA and production of fibronectin, plasminogen activator inhibitor-1 (PAI-1), TGF-beta1, and p-Smad2 protein were also reduced. The maximal therapeutic effects of 1D11 and enalapril alone were very similar. However, combination therapy led to further reduction in disease. Notably, matrix deposition was reduced by 80%. CONCLUSION: While 1D11 or enalapril at maximal doses reduce fibrosis equally, simultaneous blockade of Ang II and TGF-beta reduces fibrotic disease considerably more, offering hope that such drug combinations may confer a therapeutic advantage over angiotensin blockade alone.


Asunto(s)
Angiotensina II/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Anticuerpos Monoclonales/farmacología , Enalapril/farmacología , Glomerulonefritis/patología , Riñón/patología , Factor de Crecimiento Transformador beta/inmunología , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Animales , Anticuerpos Monoclonales/administración & dosificación , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Enalapril/administración & dosificación , Fibrosis , Glomerulonefritis/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Ratas , Ratas Sprague-Dawley
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