RESUMO
BACKGROUND: A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL. METHODS: In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed. RESULTS: Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was -2.7±1.8, 0.2±1.7, -1.5±1.8, and -7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group. CONCLUSIONS: In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo. (Funded by Visterra; ENVISION ClinicalTrials.gov number, NCT04287985; EudraCT number, 2019-002531-29.).
Assuntos
Anticorpos Monoclonais Humanizados , Glomerulonefrite por IGA , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Adulto , Humanos , Administração Intravenosa , Creatinina/urina , Método Duplo-Cego , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/genética , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Imunoglobulina GRESUMO
The pathogenic roles for B cells in autoimmunity include produce pathogenic autoantibodies and modulate immune responses via the production of cytokines and chemokines. The B lymphocyte stimulator BLyS (also known as B-cell-activating factor, BAFF) and APRIL (a proliferation-inducing ligand) are critical factors in the maintenance of the B-cell pool and humoral immunity, namely BLyS modulates the differentiation and maturation of immature B cell, while APRIL modulates the function and survival of long-lived plasma cell, which plays a prominent role in the pathogenesis of autoimmune diseases. Telitacicept is a novel recombinant fusion protein of both the ligand-binding domain of the TACI receptor and the Fc component of human IgG and which is a BLyS/APRIL dual inhibitor. Moreover, telitacicept was developed by Remegen Co., Ltd. in China and is approved to treat systemic lupus erythematosus in China. We review the rationale, clinical evidence, and future perspectives of telitacicept for the treatment of autoimmune disease.HighlightThe B lymphocyte stimulator BLyS (also known as B-cell-activating factor, BAFF) and APRIL (a proliferation-inducing ligand), members of tumor necrosis factor (TNF) family, and which are critical factors in the maintenance of the B-cell pool and humoral immunity.BAFF and APRIL are implicated in the pathogenesis of several human autoimmune diseases with autoreactive B-cell involvement, and targeting both is beneficial for the treatment of autoimmune diseases.Telitacicept is a novel recombinant fusion protein of both the ligand-binding domain of the TACI receptor and the Fc component of human IgG, as a BLyS/APRIL dual inhibitor and which has been approved by National Medical Products Administration (MNPA) for the treatment of patients with SLE in China.With more clinical trials underway, telitacicept may also be approved for the treatment of other autoimmune diseases in the future.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Fator Ativador de Células B/antagonistas & inibidores , Imunossupressores/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Doenças Autoimunes/imunologia , Fator Ativador de Células B/imunologia , Ensaios Clínicos como Assunto/métodos , Humanos , Imunossupressores/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologiaRESUMO
Chimeric antigen receptor (CAR) T cells (CARTs) have shown tremendous potential for the treatment of certain B-cell malignancies, including patients with relapsed/refractory multiple myeloma (MM). Targeting the B-cell maturation antigen (BCMA) has produced the most promising results for CART therapy of MM to date, but not all remissions are sustained. Emergence of BCMA escape variants has been reported under the selective pressure of monospecific anti-BCMA CART treatment. Thus, there is a clinical need for continuous improvement of CART therapies for MM. Here, we show that a novel trimeric APRIL (a proliferation-inducing ligand)-based CAR efficiently targets both BCMA+ and BCMA- MM. Modeled after the natural ligand-receptor pair, APRIL-based CARs allow for bispecific targeting of the MM-associated antigens BCMA and transmembrane activator and CAML interactor (TACI). However, natural ligands as CAR antigen-binding domains may require further engineering to promote optimal binding and multimerization to adequately trigger T-cell activation. We found that using a trimeric rather than a monomeric APRIL format as the antigen-binding domain enhanced binding to BCMA and TACI and CART activity against MM in vitro and in vivo. Dual-specific, trimeric APRIL-based CAR are a promising therapeutic approach for MM with potential for preventing and treating BCMA escape.
Assuntos
Antígenos de Neoplasias , Imunoterapia Adotiva , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Antígenos de Neoplasias/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Camundongos , Ligação Proteica/imunologia , Receptores de Antígenos Quiméricos/genética , Especificidade do Receptor de Antígeno de Linfócitos T , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chronic antibody mediated rejection (cAMR) remains a significant barrier to achieving long-term graft survival in kidney transplantation, which results from alloantibody production from B lymphocytes and plasma cells. APRIL (A proliferation-inducing ligand) and BLyS (B lymphocyte stimulator) are critical survival factors for B lymphocytes and plasma cells. Here we describe the results of APRIL/BLyS blockade in a murine cAMR kidney transplant model. c57/B6 mice underwent kidney transplantation with Bm12 kidneys (minor MHC mismatch), a well-described model for chronic rejection where animals cannot make donor specific antibody but rather make antinuclear antibody (ANA). Following transplantation, animals received TACI-Ig (to block APRIL and BLyS) or no treatment. Animals were continued on treatment until harvest 4 weeks following transplant. Serum was analyzed for circulating anti-nuclear autoantibodies using HEp-2 indirect immunofluorescence. Spleen and transplanted kidneys were analyzed via H&E. ANA production was significantly decreased in APRIL/BLyS blockade treated animals (p<0.0001). No significant difference in autoantibody production was found between syngeneic transplant control (B6 to B6) and APRIL/BLyS blockade treated animals (p = 0.90). Additionally, disruption of splenic germinal center architecture was noted in the APRIL/BLyS blockade treated animals. Despite the significant decrease in autoantibody production and germinal center disruption, no significant difference in lymphocyte infiltration was noted in the transplanted kidney. APRIL/BLyS blockade resulted in a significant decrease of autoantibody production and disrupted splenic germinal center formation in a chronic kidney transplant model, however in this model no difference in kidney transplant pathology was seen, which may have to do with the absence of any T cell centric immunosuppression. Regardless, these findings suggest that APRIL/BLyS blockade may play a role in decreasing antibody formation long-term in kidney transplantation. Future investigations will use APRIL/BLyS blockade in conjunction with T lymphocyte depleting agents to determine its efficacy in chronic rejection.
Assuntos
Formação de Anticorpos , Autoanticorpos/imunologia , Fator Ativador de Células B/antagonistas & inibidores , Linfócitos B/imunologia , Rejeição de Enxerto/imunologia , Transplante de Rim/métodos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Atherosclerosis is a lipid-driven chronic inflammatory disease that is modulated by many immune cell subsets, including B cells. Therefore, targeting the inflammatory component of cardiovascular disease represents a promising therapeutic strategy. In the past years, immunotherapy has revolutionized the treatment of autoimmunity and cancer. Many of these clinically used strategies target B cells. Given the multifaceted role of B cells in atherogenesis, it is conceivable that B-cell-directed therapies can modulate disease development. Here, we review clinically available B-cell-targeted therapies and the possible benefits or detrimental effects on cardiovascular disease.
Assuntos
Linfócitos B/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Aneurisma Aórtico/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Receptor do Fator Ativador de Células B/antagonistas & inibidores , Receptor do Fator Ativador de Células B/fisiologia , Linfócitos B/fisiologia , Doenças Cardiovasculares/imunologia , Humanos , Imunização , Depleção Linfocítica , Receptores de Antígenos de Linfócitos B/antagonistas & inibidores , Receptores de Antígenos de Linfócitos B/fisiologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/fisiologiaRESUMO
IgA nephropathy (IgAN) is a tonsil-related disease. We previously showed that oligodeoxynucleotides with CpG (CpG-ODN) and B-cell activation factor (BAFF) are involved in hyperproduction of IgA from tonsillar mononuclear cells of patients with IgAN (IgAN-TMCs). In this study, we focused on a proliferation-inducing ligand (APRIL), homologous to BAFF. IgAN-TMCs produced more APRIL than non IgAN-TMCs in the presence of both CpG-ODN and control-ODN. TLR9 expression was higher in B-cells of IgAN-TMCs, and treatment with CpG-ODN enhanced transmembrane activator and CAML interactor (TACI) expression. IgA production from IgAN-TMCs was inhibited by APRIL neutralization antibody or TACI blocking antibody, and enhanced by co-treatment of APRIL and CpG-ODN. Serum APRIL levels were higher in patients with IgAN, and decreased after tonsillectomy. These findings suggest that APRIL is involved in the hyperproduction of IgA from IgAN-TMCs, and that CpG-ODN enhanced APRIL-induced IgA production by increasing TACI expression on B-cells of IgAN-TMCs.
Assuntos
Linfócitos B/imunologia , Glomerulonefrite por IGA/genética , Tonsila Palatina/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Adolescente , Adulto , Idoso , Anticorpos Neutralizantes/farmacologia , Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Regulação da Expressão Gênica , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/cirurgia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Oligodesoxirribonucleotídeos/farmacologia , Tonsila Palatina/patologia , Tonsila Palatina/cirurgia , Transdução de Sinais , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologia , Tonsilectomia , Proteína Transmembrana Ativadora e Interagente do CAML/antagonistas & inibidores , Proteína Transmembrana Ativadora e Interagente do CAML/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologiaRESUMO
IgA nephropathy (IgAN) is the most prevalent primary chronic glomerular disease for which no safe disease-specific therapies currently exist. IgAN is an autoimmune disease involving the production of autoantigenic, aberrantly O-glycosylated IgA1 and ensuing deposition of nephritogenic immune complexes in the kidney. A Proliferation Inducing Ligand (APRIL) has emerged as a key B-cell-modulating factor in this pathogenesis. Using a mouse anti-APRIL monoclonal antibody (4540), we confirm both the pathogenic role of APRIL in IgAN and the therapeutic efficacy of antibody-directed neutralization of APRIL in the grouped mouse ddY disease model. Treatment with 4540 directly translated to a reduction in relevant pathogenic mechanisms including suppressed serum IgA levels, reduced circulating immune complexes, significantly lower kidney deposits of IgA, IgG and C3, and suppression of proteinuria compared to mice receiving vehicle or isotype control antibodies. Furthermore, we translated these findings to the pharmacological characterization of VIS649, a highly potent, humanized IgG2κ antibody targeting and neutralizing human APRIL through unique epitope engagement, leading to inhibition of APRIL-mediated B-cell activities. VIS649 treatment of non-human primates showed dose-dependent reduction of serum IgA levels of up to 70%. A reduction of IgA+, IgM+, and IgG+ B cells was noted in the gut-associated mucosa of VIS649-treated animals. Population-based modeling predicted a favorable therapeutic dosing profile for subcutaneous administration of VIS649 in the clinical setting. Thus, our data highlight the potential therapeutic benefit of VIS649 for the treatment of IgAN.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Glomerulonefrite por IGA/tratamento farmacológico , Imunoglobulina A/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo Antígeno-Anticorpo/efeitos dos fármacos , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Simulação por Computador , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Epitopos de Linfócito B/imunologia , Feminino , Glomerulonefrite por IGA/imunologia , Humanos , Imunoglobulina A/metabolismo , Injeções Intravenosas , Injeções Subcutâneas , Macaca fascicularis , Masculino , Camundongos , Modelos Biológicos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
BACKGROUND: Highly sensitized candidates on the transplant waitlist remain a significant challenge, as current desensitization protocols have variable success rates of donor-specific antibody (DSA) reduction. Therefore, improved therapies are needed. A proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS) are critical survival factors for B-lymphocytes and plasma cells, which are the primary sources of alloantibody production. We examined the effect of APRIL/BLyS blockade on DSA in a murine kidney transplant model as a possible novel desensitization strategy. METHODS: C57BL/6 mice were sensitized with intraperitoneal (IP) injections of 2 × 10 BALB/c splenocytes. Twenty-one days following sensitization, animals were treated with 100 µg of BLyS blockade (B-cell activating factor receptor-immunoglobulin) or APRIL/BLyS blockade (transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin), administered thrice weekly for an additional 21 days. Animals were then euthanized or randomized to kidney transplant with Control Ig, BLyS blockade, or APRIL/BLyS blockade. Animals were euthanized 7 days posttransplant. B-lymphocytes and DSA of BLyS blockade only or APRIL/BLyS blockade-treated mice were assessed by flow cytometry, immunohistochemistry, and enzyme-linked immunospot. RESULTS: APRIL/BLyS inhibition resulted in a significant reduction of DSA by flow crossmatch compared with controls (P < 0.01). APRIL/BLyS blockade also significantly depleted IgM- and IgG-secreting cells and B-lymphocyte populations compared to controls (P < 0.0001). APRIL/BLyS blockade in transplanted mice also resulted in decreased B-lymphocyte populations; however, no difference in rejection rates were seen between groups. CONCLUSIONS: APRIL/BLyS blockade with transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin significantly depleted B-lymphocytes and reduced DSA in this sensitized murine model. APRIL/BLyS inhibition may be a clinically useful desensitization strategy for sensitized transplant candidates.
Assuntos
Fator Ativador de Células B/antagonistas & inibidores , Linfócitos B/efeitos dos fármacos , Dessensibilização Imunológica , Rejeição de Enxerto/prevenção & controle , Imunoglobulinas/administração & dosagem , Isoanticorpos/imunologia , Isoantígenos/imunologia , Transplante de Rim/efeitos adversos , Baço/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Isoanticorpos/sangue , Isoantígenos/sangue , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Baço/imunologia , Baço/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fatores de Tempo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
Alloantibody represents a significant barrier in kidney transplant through the sensitization of patients prior to transplant through antibody mediated rejection (ABMR). APRIL BLyS are critical survival factors for mature B lymphocytes plasma cells, the primary source of alloantibody. We examined the effect of APRIL/BLyS blockade via TACI-Ig (Transmembrane activator calcium modulator cyclophilin lig interactor-Immunoglobulin) in a preclinical rodent model as treatment for both desensitization ABMR. Lewis rats were sensitized with Brown Norway (BN) blood for 21 days. Following sensitization, animals were then sacrificed or romized into kidney transplant (G4, sensitized transplant control); desensitization with TACI-Ig followed by kidney transplant (G5, sensitized + pre-transplant TACI-Ig); kidney transplant with post-transplant TACI-Ig for 21 days (G6, sensitized + post-transplant TACI-Ig); desensitization with TACI-Ig followed by kidney transplant post-transplant TACI-Ig for 21 days (G7, sensitized + pre- post-transplant TACI-Ig). Animals were sacrificed on day 21 post-transplant tissues were analyzed using flow cytometry, IHC, ELISPOT, RT-PCR. Sensitized animals treated with APRIL/BLyS blockade demonstrated a significant decrease in marginal zone non-switched B lymphocyte populations (p<0.01). Antibody secreting cells were also significantly reduced in the sensitized APRIL/BLyS blockade treated group. Post-transplant APRIL/BLyS blockade treated animals were found to have significantly less C4d deposition less ABMR as defined by Banff classification when compared to groups receiving APRIL/BLyS blockade before transplant or both before after transplant (p<0.0001). The finding of worse ABMR in groups receiving APRIL/BLyS blockade before both before after transplant may indicate that B lymphocyte depletion in this setting also resulted in regulatory lymphocyte depletion resulting in a worse rejection. Data presented here demonstrates that the targeting of APRIL BLyS can significantly deplete mature B lymphocytes, antibody secreting cells, effectively decrease ABMR when given post-transplant in a sensitized animal model.
Assuntos
Fator Ativador de Células B/imunologia , Dessensibilização Imunológica/métodos , Rejeição de Enxerto/prevenção & controle , Transplante de Rim , Proteínas Recombinantes de Fusão/farmacologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Animais , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/genética , Complemento C4b/antagonistas & inibidores , Complemento C4b/biossíntese , Citometria de Fluxo , Regulação da Expressão Gênica , Humanos , Imunização/métodos , Imunofenotipagem , Isoanticorpos/biossíntese , Masculino , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/biossíntese , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Plasmócitos/patologia , Ratos , Ratos Endogâmicos Lew , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
Autoimmunity occurs when an adaptive immune response is directed against a self-antigen. As such, autoimmune reactions associated with the production of autoantibodies are common. These autoantibodies may either be pathogenic by inducing the initial damage to self, or exacerbate the reaction secondarily to the initial damage. In both cases, the pathway(s) leading to exposure of the immune system to the self-antigen inducing the production of autoantibodies is largely unknown. The latter is largely complicating the setting of putative prophylactic treatments. As a consequence, one possible way to control these diseases is to eliminate the cells producing antibodies. We will see that this approach is not yet part of any treatment in autoimmunity. Indeed, all the currently available non-specific immunosuppressive treatments do not target directly quiescent antibody-producing plasma cells. However, treatments aimed at depleting precursors of plasma cells, mature B-lymphocytes and/or antigen-experienced B cells not yet fully differentiated into plasma cells, are emerging. Such strategies were recently proven to be highly successful in several autoimmune disorders by two independent ways. The first way is by induction of B-cell cytotoxicity with an antibody directed against the surface antigen CD20. The second way is by antagonism of a key B-cell survival factor, the B-cell activation factor from the TNF superfamily (BAFF). In the present review, we will focus on the current knowledge regarding the role of a molecule related to BAFF, a proliferation-inducing ligand (APRIL), in autoimmune diseases, which acts on antibody-producing plasma cells. We will discuss expectations deriving from APRIL targeting in autoimmune diseases.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/terapia , Autoimunidade/efeitos dos fármacos , Fator Ativador de Células B/imunologia , Terapia de Alvo Molecular/métodos , Plasmócitos/efeitos dos fármacos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Antígenos CD20/genética , Antígenos CD20/imunologia , Autoanticorpos , Autoantígenos/genética , Autoantígenos/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/genética , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Citotoxicidade Imunológica , Regulação da Expressão Gênica , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunossupressores/uso terapêutico , Plasmócitos/imunologia , Plasmócitos/patologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
OBJECTIVE: To evaluate the efficacy and safety of atacicept, an antagonist of B lymphocyte stimulator/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE). METHODS: ADDRESS II is a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study evaluating the safety and efficacy of atacicept in patients with SLE (ClinicalTrials.gov identifier NCT01972568). Patients with active, autoantibody-positive SLE receiving standard therapy were randomized (1:1:1) to receive atacicept (75 mg or 150 mg) or placebo for 24 weeks. The primary end point was the SLE responder index 4 (SRI-4) at week 24. RESULTS: The intent-to-treat (ITT) population included 306 patients. There was a trend toward an improved SRI-4 response rate with atacicept 75 mg (57.8%; adjusted odds ratio [OR] 1.78, P = 0.045) and 150 mg (53.8%; adjusted OR 1.56, P = 0.121) at week 24 as compared with placebo (44.0%) (primary analysis; using the screening visit as baseline). In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI-4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo. CONCLUSION: Atacicept treatment showed evidence of efficacy in SLE, particularly in HDA and serologically active patients. Reductions in disease activity and severe flare were observed with atacicept treatment, with an acceptable safety profile.
Assuntos
Fator Ativador de Células B/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Adulto , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The TNF family cytokines B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) support plasma cell survival. It is known that inhibitors of BAFF only (BAFFR-Fc) or BAFF and APRIL (TACI-Fc) administered early enough in an NZB/NZW F1 mouse model of systemic lupus erythematosus (SLE) ameliorate clinical outcomes, pointing to a pathogenic role of BAFF. In the present study, TACI-Fc administrated at a later stage of disease, after onset of autoimmunity, decreased the number of bone marrow plasma cells and slowed down further formation of autoantibodies. TACI-Fc prevented renal damage during a 12-week treatment period regardless of autoantibody levels, while BAFFR-Fc did not despite a similar BAFF-blocking activity in vivo. TACI-Fc also decreased established plasma cells in a T-dependent hapten/carrier immunization system better than single inhibitors of BAFF or APRIL, and sometimes better than combined single inhibitors with at least equivalent BAFF and APRIL inhibitory activities. These results indicate that TACI-Fc can prevent symptoms of renal damage in a mouse model of SLE when BAFFR-Fc cannot, and point to a plasticity of plasma cells for survival factors. Targeting plasma cells with TACI-Fc might be beneficial to prevent autoantibody-mediated damages in SLE.
Assuntos
Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/imunologia , Plasmócitos/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/administração & dosagem , Animais , Autoanticorpos/biossíntese , Autoimunidade , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/administração & dosagem , Receptor do Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Citometria de Fluxo , Rim/imunologia , Rim/patologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Lúpus Eritematoso Sistêmico/terapia , Camundongos , Plasmócitos/patologia , Proteína Transmembrana Ativadora e Interagente do CAML/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologiaRESUMO
It is well documented that A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily, plays a crucial role in the occurrence and development of tumors. In the present study, we evaluated the synergistic effect of APRIL knockdown and Jiedu Xiaozheng Yin (JXY), a Traditional Chinese Medicinal recipe, on the inhibition of hepatocellular carcinoma (HCC) cell proliferation and elucidated the underlying mechanism. The results demonstrated that both APRIL knockdown using small interfering RNA (siRNA) and JXY treatment could trigger cell cycle arrest and cell apoptosis, and suppress HCC cell proliferation through an NF-κB-related pathway. Synergism was further demonstrated between APRIL knockdown and JXY treatment. In conclusion, these results indicate that APRIL is a target gene for HCC and combination of siRNA-APRIL and JXY application holds great promise as a novel approach for the treatment of APRIL-positive HCC.
Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Neoplasias Hepáticas/patologia , Extratos Vegetais/farmacologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Apoptose/genética , Western Blotting , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Terapia Combinada , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Masculino , Camundongos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
B cells may have a negative regulatory role, mainly mediated by interleukin 10 (IL-10). We recently showed that regulatory B-cell functions are impaired in patients with rheumatoid arthritis (RA) and that mice transgenic for a proliferation-inducing ligand (APRIL) are protected against collagen-induced arthritis. We aimed to explore the effect of APRIL on human B-cell IL-10 production, in healthy subjects and in patients with RA. The IL-10 production of B-cell was greater with APRIL than with BLyS or control medium, in a dose dependent manner. TACI expression was greater in IL-10 producing B cells (B10) than non-IL-10-producing B cells whereas BAFF-R expression was lower. TNF-α and IFN-γ secretion of T-cells were decreased by APRIL-stimulated B cells. APRIL stimulated STAT3 and STAT3 inhibition decreased B10 cells. APRIL also promoted B10 cells in RA patients. In conclusion, APRIL but not BLyS promotes IL-10 production by CpG-activated B cells and enhances the regulatory role of B cells on T cells. B10 cells in RA patients are responsive to APRIL, which suggests a possible therapeutic application of APRIL to expand B10 cells. This could also explain the difference of clinical efficacy observed between belimumab and atacicept in RA.
Assuntos
Artrite Reumatoide/imunologia , Linfócitos B Reguladores/imunologia , Linfócitos B Reguladores/metabolismo , Interleucina-10/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Autoimunidade/imunologia , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B Reguladores/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-10/imunologia , Leucócitos Mononucleares , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Oligodesoxirribonucleotídeos/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linfócitos T/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The importance of B cell activating factors in the generation of autoantibodies in patients with systemic lupus erythematosus (SLE) is now recognized. The two key factors, known as BAFF and APRIL, produced by a variety of cells including monocytes, dendritic cells and T cells, also help to regulate B cell maturation, function and survival. Biologic agents that block these factors have now been developed and tried out in large scale clinical trials in SLE patients. Benlysta which blocks BAFF has met some of its end points in clinical trials and is approved for use in patients with skin and joint disease who have failed conventional drugs. In contrast, clinical trials using atacicept which blocks both BAFF and APRIL have been more challenging to interpret. An early study in lupus nephritis was, mistakenly, abandoned due to serious infections thought to be linked to the biologic when in fact the dramatic fall in the immunoglobulin levels took place when the patients were given mycophenolate, prior to the introduction of the atacicept. Likewise the higher dose arm (150 mgm) of a flare prevention study was terminated prematurely when 2 deaths occurred. However, the mortality rate in this study was identical to that seen in the Benlysta studies and a post hoc analysis found a highly significant benefit for the 150mgm arm compared to the lower dose (75 mgm) and placebo arms. Other trials with both Benlysta and atacicept are on-going.
Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Fator Ativador de Células B/antagonistas & inibidores , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Humanos , Proteínas Recombinantes de Fusão/farmacologia , Relação Estrutura-Atividade , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidoresRESUMO
The "A proliferation inducing ligand" protein (APRIL) is a cytokine over-expressed in many transformed and tumoral cells acting onto two distinct receptors of the Tumoral Necrosis Factor B cell maturation antigen (BCMA) and the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). We herein describe, through a detailed computational approach, the molecular interactions between TACI and its ligands APRIL and another structurally similar protein called B-cell activating factor (BAFF) by means of molecular dynamics. Dynamical analysis suggests R84 and D85 residues from TACI as possible mutation candidates, yielding increased affinity between TACI and APRIL. The association of computational simulations, site directed mutagenesis and peptide design could be a powerful tool, driving to better in vitro experiments. Our results contribute to the elucidation of APRIL signaling and help clarify the effects of blocking interaction between APRIL and its receptors through the use of particular peptides.
Assuntos
Fator Ativador de Células B/metabolismo , Peptídeos/farmacologia , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Sequência de Aminoácidos , Animais , Fator Ativador de Células B/química , Desenho de Fármacos , Humanos , Técnicas de Imunoadsorção , Ligantes , Camundongos , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Peptídeos/química , Ligação Proteica/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteína Transmembrana Ativadora e Interagente do CAML/química , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/químicaRESUMO
In recent years, significant progress has been made in the use of monoclonal antibodies in the treatment of systemic lupus erythematosus (SLE). Advances in our understanding of the complexity of SLE immunopathogenesis have led to the testing of several biologic agents in clinical trials. Monoclonal therapies currently emerging or under development include B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anticytokine therapies. Issues remain, however, regarding clinical trial design and outcome measures in SLE which need to be addressed to optimize translation of these promising therapies into clinical practice.
Assuntos
Linfócitos B/imunologia , Terapia Biológica/tendências , Lúpus Eritematoso Sistêmico/terapia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Fator Ativador de Células B/antagonistas & inibidores , Linfócitos B/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Interferon-alfa/uso terapêutico , Lúpus Eritematoso Sistêmico/imunologia , Depleção Linfocítica , Receptor Cross-Talk/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Pesquisa Translacional Biomédica , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidoresRESUMO
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises several clinical entities with diverse clinical presentations, outcomes, and nonunifying pathogenesis. AAV has a clear potential for relapses, and shows unpredictable response to treatment. Cyclophosphamide-based therapies have remained the hallmark of induction therapy protocols for more than four decades. Recently, B-cell depleting therapy with the anti-CD20 antibody rituximab has proved beneficial in AAV, leading to Food and Drug Administration approval of rituximab in combination with corticosteroids for the treatment of AAV in adults. Rituximab for ANCA-associated vasculitis and other clinical trials provided clear evidence that rituximab was not inferior to cyclophosphamide for remission induction, and rituximab appeared even more beneficial in patients with relapsing disease. This raised hopes that other B-cell-targeted therapies directed either against CD19, CD20, CD22, or B-cell survival factors, B-cell activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand could also be beneficial for the management of AAV. BAFF neutralization with the fully humanized monoclonal antibody belimumab has already shown success in human systemic lupus erythematosus and, along with another anti-BAFF reagent blisibimod, is currently undergoing Phase II and III clinical trials in AAV. Local production of BAFF in granulomatous lesions and elevated levels of serum BAFF in AAV provide a rationale for BAFF-targeted therapies not only in AAV but also in other forms of vasculitis such as Behcet's disease, large-vessel vasculitis, or cryoglobulinemic vasculitis secondary to chronic hepatitis C infection. BAFF-targeted therapies have a very solid safety profile, and may have an additional benefit of preferentially targeting newly arising autoreactive B cells over non-self-reactive B cells.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fator Ativador de Células B/antagonistas & inibidores , Linfócitos B/efeitos dos fármacos , Descoberta de Drogas/métodos , Imunossupressores/uso terapêutico , Terapia de Alvo Molecular/métodos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
Pancreatic adenocarcinoma (PA) is a leading cause of adult cancer mortality, and surgery is still the best available treatment strategy. However, PA can recur at any time and has limited prognosis. It is therefore necessary to explore novel serum biomarkers of PA to allow the early diagnosis of PA. Soluble a-proliferation-inducing ligand (sAPRIL), a promising inducer of the epithelial-mesenchymal transition (EMT), is often found overexpressed in a variety of autoimmune diseases. To determine whether serum sAPRIL can constitute a PA biomarker, the protein level of sAPRIL was examined by immunohistochemistry and western blot, and the mRNA level was quantified by RT-qPCR. The PA cell line PanC-1 was transfected with vectors bearing the sAPRIL gene and sAPRIL short hairpin RNA (shRNA) oligos. Increased expression of serum sAPRIL was observed in patients with PA recurrence or metastasis after five-year surgery compared to subjects without PA recurrence or metastasis. The growth rate of PanC-1 cells transfected with the sAPRIL expression vector was increased by 23% (P<0.01, vs. control group), and was reduced by 17% (P<0.01, vs. control group) in the sAPRIL shRNA-silenced cell line. Thus, sAPRIL is highly expressed in PA, and serum levels of sAPRIL can serve as a useful indicator for the recurrence or metastasis of PA after surgery. Additional validation studies on the use of serum sAPRIL as a diagnostic marker in PA are however needed.
Assuntos
Adenocarcinoma/patologia , Neoplasias Pancreáticas/patologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Idoso , Biomarcadores/sangue , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Vetores Genéticos/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirurgia , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transfecção , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
A proliferation-inducing ligand (APRIL) is a key cell proliferation-regulatory molecule and have been investigated well enough in immunity regulation and a few of immune diseases. APRIL can stimulate tumor cell growth and is up-expressed in cancer tissues, especially in CRC (colorectal cancer). However, whether inhibition of APRIL can regulate tumor-relative genes expression in vivo and subsequently ameliorate the pathological progress of CRC remains obscure. To address this question, we developed a novel negative lipidoid nanoparticles (NLNs) encapsulating small interference RNA (siRNA) for selectively silencing APRIL in the parenchyma of CRC focus in vivo, which uptake proceeded through a lipid raft endocytotic pathway. Local enema delivery of APRIL-NLNs silenced APRIL in CRC cells and animal models, and then ameliorated experimentally the progress of CRC by suppressing CRC cell proliferation, metastasis, and apoptosis-related cytokine expression and did not affect the function of liver and kidneys and not trigger the immune response of CRC models. This study reveals APRIL to be a potential anti-CRC target by in vivo experiments, and suggests that the application of similar modes of siRNA delivery may be feasible in other therapeutic settings.