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1.
Front Immunol ; 9: 1613, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123214

RESUMO

Agents targeting the PD1-PDL1 axis have transformed cancer therapy. Factors that influence clinical response to PD1-PDL1 inhibitors include tumor mutational burden, immune infiltration of the tumor, and local PDL1 expression. To identify peripheral correlates of the anti-tumor immune response in the absence of checkpoint blockade, we performed a retrospective study of circulating T cell subpopulations and matched tumor gene expression in melanoma and non-small cell lung cancer (NSCLC) patients. Notably, both melanoma and NSCLC patients whose tumors exhibited increased inflammatory gene transcripts presented high CD4+ and CD8+ central memory T cell (CM) to effector T cell (Eff) ratios in blood. Consequently, we evaluated CM/Eff T cell ratios in a second cohort of NSCLC. The data showed that high CM/Eff T cell ratios correlated with increased tumor PDL1 expression. Furthermore, of the 22 patients within this NSCLC cohort who received nivolumab, those with high CM/Eff T cell ratios, had longer progression-free survival (PFS) (median survival: 91 vs. 215 days). These findings show that by providing a window into the state of the immune system, peripheral T cell subpopulations inform about the state of the anti-tumor immune response and identify potential blood biomarkers of clinical response to checkpoint inhibitors in melanoma and NSCLC.

2.
JCI Insight ; 1(9): e87310, 2016 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-27699274

RESUMO

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease driven by both innate and adaptive immune cells. African Americans tend to present with more severe disease at an earlier age compared with patients of European ancestry. In order to better understand the immunological differences between African American and European American patients, we analyzed the frequencies of B cell subsets and the expression of B cell activation markers from a total of 68 SLE patients and 69 normal healthy volunteers. We found that B cells expressing the activation markers CD86, CD80, PD1, and CD40L, as well as CD19+CD27-IgD- double-negative B cells, were enriched in African American patients vs. patients of European ancestry. In addition to increased expression of CD40L, surface levels of CD40 on B cells were lower, suggesting the engagement of the CD40 pathway. In vitro experiments confirmed that CD40L expressed by B cells could lead to CD40 activation and internalization on adjacent B cells. To conclude, these results indicate that, compared with European American patients, African American SLE patients present with a particularly active B cell component, possibly via the activation of the CD40/CD40L pathway. These data may help guide the development of novel therapies.


Assuntos
Linfócitos B/citologia , Lúpus Eritematoso Sistêmico/etnologia , Afro-Americanos , Antígenos de Superfície/análise , Antígeno B7-2/análise , Antígenos CD40/análise , Ligante de CD40/análise , Humanos , Fenótipo
3.
J Mol Biol ; 428(14): 2860-79, 2016 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-27216500

RESUMO

Current clinical anti-CD40 biologic agents include both antagonist molecules for the treatment of autoimmune diseases and agonist molecules for immuno-oncology, yet the relationship between CD40 epitope and these opposing biological outcomes is not well defined. This report describes the identification of potent antagonist domain antibodies (dAbs) that bind to a novel human CD40-specific epitope that is divergent in the CD40 of nonhuman primates. A similarly selected anti-cynomolgus CD40 dAb recognizing the homologous epitope is also a potent antagonist. Mutagenesis, biochemical, and X-ray crystallography studies demonstrate that the epitope is distinct from that of CD40 agonists. Both the human-specific and cynomolgus-specific molecules remain pure antagonists even when formatted as bivalent Fc-fusion proteins, making this an attractive therapeutic format for targeting hCD40 in autoimmune indications.


Assuntos
Antígenos CD40/imunologia , Epitopos/imunologia , Animais , Doenças Autoimunes/imunologia , Cristalografia por Raios X/métodos , Humanos , Macaca fascicularis
4.
Bioorg Med Chem Lett ; 26(10): 2470-2474, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27055941

RESUMO

The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Relação Estrutura-Atividade , Administração Oral , Animais , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Contagem de Linfócitos , Masculino , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistas
5.
J Med Chem ; 59(6): 2820-40, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-26924461

RESUMO

Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.


Assuntos
Isoxazóis/síntese química , Isoxazóis/farmacologia , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Animais , Artrite Experimental/tratamento farmacológico , Células CHO , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Descoberta de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Humanos , Imunossupressores/síntese química , Imunossupressores/farmacologia , Sistema Linfático/citologia , Sistema Linfático/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Esfingosina/agonistas , Relação Estrutura-Atividade , Timo/citologia , Timo/efeitos dos fármacos
6.
J Pharmacol Exp Ther ; 355(3): 506-15, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26442523

RESUMO

BMS-931699 (lulizumab pegol), a domain antibody (dAb) conjugated with 40-kDa branched polyethylene glycol, is a human anti-CD28 receptor antagonist under development for the treatment of inflammatory and autoimmune diseases. In the present work, the minimal anticipated biologic effect level (MABEL) was determined for BMS-931699 by integrating all the available preclinical data. The relevance of the in vitro mixed lymphocyte reaction (MLR) assay to a whole blood CD28 receptor occupancy (RO) assessment, as well as the relationship between the CD28 RO and the inhibition of T-cell-dependent antibody response to keyhole limpet hemocyanin in vivo, was demonstrated through an integrated pharmacokinetic/pharmacodynamic analysis using anti-hCD28 dAb-001 (differing from BMS-931699 by two additional amino acids at the N-terminus) and a mouse surrogate. Based on this analysis, the EC10 value (0.32 nM) from the human MLR assay and the human plasma volume (0.04 l/kg) were employed to calculate the MABEL (0.01 mg) of BMS-931699 in humans, with a CD28 RO predicted to be ≤10%. The estimated MABEL dose was threefold higher than the value derived from the binding constant and twofold less than the MABEL converted from animal efficacy studies based on the body surface area. Furthermore, it was 2900-fold lower than the human equivalent dose derived from the no observed adverse effect level in monkeys (15 mg/kg/week for 5 doses, intravenous dosing) with a 10-fold safety factor applied. Therefore, the MABEL dose represented a sound approach to mitigate any potential risk in targeting CD28 and was successfully used as the first-in-human starting dose for BMS-931699.


Assuntos
Anticorpos/farmacologia , Antígenos CD28/antagonistas & inibidores , Polietilenoglicóis/farmacologia , Polietilenoglicóis/farmacocinética , Algoritmos , Animais , Superfície Corporal , Relação Dose-Resposta a Droga , Feminino , Hemocianinas/antagonistas & inibidores , Humanos , Teste de Cultura Mista de Linfócitos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Testes de Sensibilidade Microbiana , Monócitos/efeitos dos fármacos
7.
PLoS One ; 10(6): e0130490, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26098894

RESUMO

Programmed T cell differentiation is critically influenced by the complement of costimulatory and coinhibitory signals transmitted during initial antigen encounter. We previously showed that selective CD28 blockade with novel domain antibodies that leave CTLA-4-mediated coinhibitory signaling intact resulted in more profound attenuation of donor-reactive T cell responses and improved graft survival in a murine transplant model. Selective CD28 blockade was also associated with decreased ICOS expression on donor-reactive CD8+ T cell responses as compared to CTLA-4 Ig, but the functional importance of this reduced ICOS expression was not known. In this study, we created retrogenic donor-reactive CD8+ T cells that overexpress ICOS in order to determine whether reduced ICOS expression mechanistically underlies the increased efficacy of selective CD28 blockade in controlling graft-specific T cell responses as compared to conventional costimulation blockade with CTLA-4 Ig. Results indicated that the ability of selective CD28 blockade to blunt donor-reactive CD8+ T cell expansion following transplantation was independent of its ability to inhibit ICOS expression. Furthermore, we have previously published that 2B4 coinhibitory signals are functionally important for controlling graft-specific CD8+ T cell responses in mice treated with CD28 blockade. Here we used a co-adoptive transfer approach to determine that 2B4 coinhibitory signals on antigen-specific CD8+ T cells function in a cell-intrinsic manner to limit ICOS expression in the setting of selective CD28 blockade.


Assuntos
Antígenos CD28/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Animais , Antígenos CD28/antagonistas & inibidores , Reação Hospedeiro-Enxerto , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
8.
J Exp Med ; 211(2): 297-311, 2014 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-24493803

RESUMO

Mounting evidence in models of both autoimmunity and chronic viral infection suggests that the outcome of T cell activation is critically impacted by the constellation of co-stimulatory and co-inhibitory receptors expressed on the cell surface. Here, we identified a critical role for the co-inhibitory SLAM family member 2B4 (CD244) in attenuating primary antigen-specific CD8(+) T cell responses in the presence of immune modulation with selective CD28 blockade. Our results reveal a specific up-regulation of 2B4 on antigen-specific CD8(+) T cells in animals in which CD28 signaling was blocked. However, 2B4 up-regulation was not observed in animals treated with CTLA-4 Ig (abatacept) or CD28 blockade in the presence of anti-CTLA-4 mAb. 2B4 up-regulation after CD28 blockade was functionally significant, as the inhibitory impact of CD28 blockade was diminished when antigen-specific CD8(+) T cells were deficient in 2B4. In contrast, 2B4 deficiency had no effect on CD8(+) T cell responses during unmodified rejection or in the presence of CTLA-4 Ig. We conclude that blockade of CD28 signals in the presence of preserved CTLA-4 signals results in the unique up-regulation of 2B4 on primary CD8(+) effectors, and that this 2B4 expression plays a critical functional role in controlling antigen-specific CD8(+) T cell responses.


Assuntos
Antígenos CD/biossíntese , Antígenos CD28/antagonistas & inibidores , Linfócitos T CD8-Positivos/imunologia , Receptores Imunológicos/biossíntese , Abatacepte , Aloenxertos , Animais , Anticorpos Monoclonais/administração & dosagem , Antígenos CD/genética , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Sobrevivência de Enxerto/imunologia , Imunoconjugados/administração & dosagem , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Imunológicos , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Transdução de Sinais/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária , Transplante de Pele , Regulação para Cima
9.
J Immunol ; 191(9): 4599-610, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24081989

RESUMO

Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 ± 14 ng/ml for inhibition of proliferation. The EC50 of 53 ± 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4-mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell-dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases.


Assuntos
Antígeno B7-1/imunologia , Antígeno B7-2/imunologia , Antígenos CD28/antagonistas & inibidores , Antígenos CD28/imunologia , Linfócitos T/imunologia , Animais , Anticorpos/imunologia , Células Apresentadoras de Antígenos/imunologia , Doenças Autoimunes/terapia , Antígeno CTLA-4/imunologia , Proliferação de Células , Humanos , Ativação Linfocitária/imunologia , Macaca fascicularis
10.
J Med Chem ; 53(9): 3814-30, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20405922

RESUMO

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.


Assuntos
Hidantoínas/farmacocinética , Fatores Imunológicos/química , Antígeno-1 Associado à Função Linfocitária/efeitos dos fármacos , Ácidos Nicotínicos/farmacocinética , Humanos , Hidantoínas/farmacologia , Antígeno-1 Associado à Função Linfocitária/química , Antígeno-1 Associado à Função Linfocitária/imunologia , Ácidos Nicotínicos/toxicidade , Relação Estrutura-Atividade
11.
J Immunol ; 184(7): 3917-26, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20190141

RESUMO

LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Inflamação/tratamento farmacológico , Antígeno-1 Associado à Função Linfocitária/metabolismo , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Humanos , Inflamação/imunologia , Inflamação/patologia , Teste de Cultura Mista de Linfócitos , Antígeno-1 Associado à Função Linfocitária/imunologia , Camundongos
12.
Transplantation ; 87(6): 926-33, 2009 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-19300198

RESUMO

BACKGROUND: The selective inhibitor of T-cell costimulation, belatacept, blocks CD28-mediated T-cell activation by binding CD80 and CD86 on antigen-presenting cells. Understanding the extent to which belatacept binds to its targets in patients may enable correlation of belatacept exposure to receptor saturation as a pharmacodynamic measure of costimulation blockade. METHODS: Flow cytometry-based receptor competition assays were developed to monitor concentration-dependent occupancy of CD80 and CD86 receptors in whole blood and dendritic cell cultures in vitro. Receptor occupancy was correlated with inhibition of mixed leukocyte reactions and clinical validation was obtained by comparing receptor saturation in whole blood from healthy volunteers and in de novo renal transplant recipients participating in studies comparing cyclosporine and belatacept-based immunosuppression. RESULTS: Belatacept saturated CD80 and CD86 receptors in whole blood and dendritic cell cultures, although the belatacept concentrations required for CD86-receptor saturation were approximately 10-fold higher than those required for CD80 saturation (IC50=0.102 microg/mL vs. 0.009 microg/mL). Primary alloresponses were inhibited at the belatacept concentration required for CD86-receptor saturation, but not at the lower concentration needed to saturate CD80. Whole blood from belatacept-treated patients had significantly lower levels of free CD86 receptors versus pretransplant levels, healthy volunteers, or cyclosporine-treated patients. CD86-receptor saturation correlated with belatacept dose/dose frequency and remained consistently more than 80%. CONCLUSIONS: These results suggest that belatacept-mediated inhibition of alloresponses involved in transplant rejection correlates with CD86 saturation, indicating that CD86-receptor occupancy may be a valid pharmacodynamic measure of costimulation blockade and provide the first direct clinical evidence that belatacept binds to one of its targets.


Assuntos
Antígeno B7-1/imunologia , Antígeno B7-2/imunologia , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Abatacepte , Animais , Antígenos CD/imunologia , Ciclosporina/uso terapêutico , Células Dendríticas/imunologia , Citometria de Fluxo , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Humanos , Imunoconjugados/farmacologia , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Monócitos/imunologia , Distribuição Aleatória , Receptores de Antígenos de Linfócitos T/efeitos dos fármacos , Ovinos
13.
J Clin Immunol ; 29(4): 479-89, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19259798

RESUMO

BACKGROUND: It has been proposed that ligation of CD80 and CD86 induces reverse signaling into antigen-presenting cells. In this study, we tested the ability of abatacept, a soluble human fusion protein comprising the extracellular domain of cytotoxic T lymphocyte antigen 4 and a fragment of the Fc domain of IgG(1), to activate antigen-presenting cells by measuring changes in global transcriptional responses. METHODS: Affymetrix chips were used to measure gene expression levels using mRNA isolated from immature and mature human dendritic cells and a B cell line following 6 h of treatment with abatacept. RESULTS: In contrast to robust transcriptional responses induced by the control treatment phorbol-12-myristate-13-acetate, abatacept induced minimal gene changes in three different populations of antigen-presenting cells. Furthermore, no gene changes were observed in response to belatacept, a modified version of abatacept that binds with higher avidity to CD80 and CD86. CONCLUSIONS: We conclude that reverse signaling in antigen-presenting cells is unlikely to occur in response to either abatacept or belatacept, thereby supporting the modulation of CD28 signaling on T cells as the main mechanism of action for these therapeutics.


Assuntos
Apresentação do Antígeno/efeitos dos fármacos , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Células Dendríticas/efeitos dos fármacos , Imunoconjugados/farmacologia , Imunossupressores/farmacologia , Abatacepte , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Antígeno B7-1/imunologia , Antígeno B7-2/imunologia , Linhagem Celular Tumoral , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/imunologia , Expressão Gênica/efeitos dos fármacos , Humanos , Ésteres de Forbol/farmacologia
14.
Clin Immunol ; 126(1): 38-47, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17945538

RESUMO

Abatacept, the first in a new class of agents for RA, modulates CD28-mediated T-cell costimulation. Abatacept was evaluated for its ability to regulate human T-cell proliferation and cytokine production initiated by dendritic cells. Abatacept reduced T-cell proliferation by >95% at concentrations between 0.3 and 3 microg/ml. The effect of abatacept on T-cell proliferation was not through induction of IDO activity, as no increase in IDO mRNA or kynurenine was observed and 1-methyl-D-tryptophan did not reverse the inhibition. In addition to the effect of abatacept on proliferation, T-cell cytokines, IL-2, TNFalpha and IFNgamma were also reduced. Abatacept also inhibited proliferation and cytokine production in a T-cell memory response. These data demonstrate that abatacept, independent of IDO activity, attenuates both naive and memory T-cell proliferation and effector function. Taken together, these data aid our understanding of the mechanism for efficacy of abatacept in patients with autoimmune disease.


Assuntos
Células Dendríticas/imunologia , Imunoconjugados/farmacologia , Imunossupressores/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Abatacepte , Proliferação de Células , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/enzimologia , Humanos , Memória Imunológica , Cinurenina/metabolismo , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , RNA Mensageiro/metabolismo , Toxoide Tetânico/imunologia
15.
J Rheumatol ; 34(11): 2204-10, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17787038

RESUMO

OBJECTIVE: To assess the ability of abatacept to mediate complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC) of antigen-presenting cells, and to characterize the binding of abatacept to the 3 Fc receptor classes. METHODS: CDC was measured in vitro using rabbit, baby rabbit, guinea pig, or human complement with human B cell line PM-LCL as the target. ADCC was also measured with PM-LCL target cells, but with human peripheral blood mononuclear cells from 12 healthy blood donors as effectors. Fc receptor binding was analyzed in vitro by flow cytometry and surface plasmon resonance (SPR). RESULTS: In contrast to unmodified CTLA4-Ig, abatacept did not mediate CDC or ADCC of target B cells. While abatacept was found to bind its target receptor, CD80/86, it did not appreciably bind the low-affinity Fc receptors CD16 and CD32 as measured by flow cytometry and SPR. Abatacept was found to minimally bind the high-affinity Fc receptor CD69 as measured by flow cytometry and SPR with a Kd of 3 X 10-7 M as measured by SPR. CONCLUSION: Abatacept does not mediate CDC or ADCC of target B cells in vitro and has limited Fc receptor binding. These data support the concept that abatacept therapeutic activity is primarily due to the binding to CD80/86 through the CTLA4 extracellular domain and not through activities mediated by the modified Fc domain.


Assuntos
Citotoxicidade Imunológica/efeitos dos fármacos , Imunoconjugados/metabolismo , Imunoconjugados/farmacologia , Receptores de IgG/metabolismo , Abatacepte , Sequência de Aminoácidos , Animais , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Linhagem Celular , Proteínas do Sistema Complemento/metabolismo , Cobaias , Humanos , Imunoconjugados/genética , Imunoglobulina G/genética , Técnicas In Vitro , Dados de Sequência Molecular , Coelhos , Homologia de Sequência de Aminoácidos
16.
Bioorg Med Chem Lett ; 17(7): 1908-11, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17291752

RESUMO

A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in vitro activity, we present the X-ray crystal structure of the complex of compound 9b, in a novel binding mode to the I-domain of LFA-1.


Assuntos
Química Farmacêutica/métodos , Antígeno-1 Associado à Função Linfocitária/química , Pirróis/química , Cristalografia por Raios X , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Estereoisomerismo , Temperatura Ambiente , Raios X
17.
J Med Chem ; 49(24): 6946-9, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-17125246

RESUMO

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.


Assuntos
Antígeno-1 Associado à Função Linfocitária/metabolismo , Compostos de Espiro/síntese química , Tiofenos/síntese química , Animais , Adesão Celular/efeitos dos fármacos , Cristalografia por Raios X , Cães , Rejeição de Enxerto/prevenção & controle , Humanos , Antígeno-1 Associado à Função Linfocitária/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia , Transplante Homólogo
18.
Bioorg Med Chem Lett ; 15(4): 1161-4, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15686933

RESUMO

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.


Assuntos
Hidantoínas/síntese química , Antígeno-1 Associado à Função Linfocitária/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Desenho de Drogas , Células HeLa , Humanos , Hidantoínas/farmacologia , Inflamação/tratamento farmacológico , Concentração Inibidora 50 , Molécula 1 de Adesão Intercelular/química , Antígeno-1 Associado à Função Linfocitária/química , Conformação Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
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