BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models / 医学前沿

OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

Research progress on OX40/OX40L axis mediated T cell immunity in the course of oral lichen planus / 口腔疾病防治

@#Oral lichen planus (OLP) is a common chronic disease of the oral mucosa with unclear pathogenesis. Local infiltration of T cells plays a key role in the pathological process of OLP. Increased evidence supports the notion that the imbalance of helper T cells (Th) 1/Th2 and Th17/regulatory T cells (Treg) and their related cytokines is closely related to the pathogenesis and progression of OLP. In recent years, studies have shown that OX40 (CD134) and its ligand OX40L (CD252) play an important role in the process of the T-cell immune response. They participate in the balance regulation of Th1/Th2 and Th17/Treg, mediate the imbalance of pro-inflammatory and anti-inflammatory, and affect the occurrence and development of a variety of autoimmune diseases. However, there is no direct evidence that the OX40/OX40L axis mediates the imbalance of T-cell subsets in the pathogenesis of OLP. Therefore, large sample clinical as well as in vitro and in vivo experimental studies on the mechanism by which the OX40/OX40L axis regulates the balance of T-cell subsets in OLP are still needed in the future.

Association of TNFSF4 polymorphisms with systemic lupus erythematosus: a meta-analysis

Abstract Objective: To more precisely estimate the association between the tumor necrosis factor ligand superfamily member 4 (TNFSF4) gene polymorphisms and systemic lupus erythematosus (SLE) susceptibility, we performed a metaanalysis on the association of the following single nucleotide polymorphisms (SNPs) of TNFSF4 with SLE: rs1234315, rs844648, rs2205960, rs704840, rs844644, rs10489265. Methods: A literature-based search was conducted using PubMed, MEDLINE, Embase, Web of Science databases, and Cochrane Library databases to identify all relevant studies. And the association of TNFSF4 gene polymorphisms and SLE susceptibility was evaluated by pooled odds ratio (OR) with 95% confidence interval (CI). Results: The meta-analysis produced overall OR of 1.42 (95% CI 1.36-1.49, P < 0.00001), 1.41 (95% CI 1.36-1.46, P < 0.00001) and 1.34 (95% CI 1.26-1.42, P < 0.00001) for the rs2205960, rs1234315 and rs704840 polymorphisms respectively, confirming these three SNPs confer a significant risk for the development of SLE. On the other hand, the meta-analysis produced overall OR of 0.92 (95% CI 0.70-1.21, P = 0.54) for the rs844644 polymorphism, suggesting no significant association. And no association was also found between either rs844648 1.11 (OR 1.11, 95% CI 0.86-1.43, P = 0.41) or rs10489265 (OR 1.17,95% CI 0.94-1.47, P = 0.17) polymorphism with SLE susceptibility, respectively. Conclusions: Our meta-analysis demonstrated that the TNFSF4 rs2205960, rs1234315 and rs844840 SNPs was significantly associated with an increased risk of SLE.

Research progress in OX40/OX40L-induced transplantation tolerance / 中华微生物学和免疫学杂志

OX40 (CD134) is a costimulatory molecule on the surface of T cells. It binds to OX40L (CD252) that is expressed on the surface of antigen presenting cells (APC) and participates in the transmission of the second signal of T cell activation, indicating that it is of great importance to the proliferation, differentiation, survival and migration of T cells. In theory, blocking the OX40/OX40L costimulatory pathway can suppress immune response and induce immune tolerance. In this review, we reviewed the research progress in OX40/OX40L-induced transplantation tolerance.

Relationship between Prognosis and Level of Plasma OX40L in Patients with Stable Angina Pectoris after Percutaneous Coronary Intervention / 中国医科大学学报

Objective To observe the ehanges in plasma OX40L level in patients with stable angina pectoris (SAP) after percutaneous coronary intervention (PCI) and to investigate the relationship between OX40L level and prognosis in patients with SAP.Methods We collected 200 cases of SAP after PCI.Plasma OX40L levels were examined at different time points,including before and after stent placement,in all patients withSAP.The patients with SAP were followed up for 18 months,and the end point was adverse cardiovascular events.Results The plasma OX40L level increased more apparently after PCI than before PCI (P ＜ 0.05) and peaked at 24 hours.We followed up 185 patients successfully,including 39 (21.08％) patients with and 146 (78.92％) without adverse cardiovascular events.The mean maximum OX40L level was higher in patients with than in those without adverse events (P ＜ 0.05).Multivariable logistic regression analysis revealed that the mean maximum OX40L level was related to adverse cardiovascular events (P ＜ 0.05).Conclusion PCI may cause upregulation of plasma OX40L expression.Mean maximum OX40L level showed good clinical predictive value of occurrence of cardiovascular events 18 months after PCI.

Ag85B regulates myeloid dendritic cell maturation and suppresses expres-sion of TSLPR and OX40L mediated by TSLP in vitro / 中国病理生理杂志

AIM:To investigate the maturation of mice immature myeloid dendritic cells (mDCs) induced by antigen(Ag)85B of mycobacterium tuberculosis, and the expression of TSLPR and OX40L mediated by TSLP in vitro. METHODS:Recombinant mouse GM-CSF ( rmGM-CSF) and rmIL-4 were used to induce bone marrow precursor cells of C57BL/6 mice to differentiate into immature mDCs in vitro.mDCs were identified followed by purification using CD 11c binding magnetic beads .The morphological characteristic of mDCs was observed under inverted phase-contrast microscope and scanning electron microscope .The surface phenotypes of mDCs were determined by flow cytometry .To obtain the opti-mal concentrations of Ag85B and TSLP, immature mDCs were cultured with different concentrations of Ag 85B or TSLP at 0 (control group), 50, 100 and 200 μg/L for 24 h, and the expression of cell surface molecules CD 80, CD86, TSLPR and OX40L was detected by flow cytometry.In addition, the expression of TSLPR and OX40L in Ag85B and TSLP-co-stimula-ted mDCs was determined by flow cytometry .RESULTS:After 7 d of culture in vitro, the cells showed irregular dendritic protrusions under the inverted-phase contrast microscope , and had wrinkles and dendritic splits under scanning electron mi-croscope , conformed to the morphological characteristics of immature mDCs .The mDCs cells expressed higher level of spe-cific marker CD11c, lower level of co-stimulatory molecules CD80 and CD86, which conformed to the phenotype of imma-ture mDCs.The CD80 +and CD86 +cell ratios of mDCs displayed significant increases in 50, 100 and 200μg/L Ag85B or TSLP groups compared with control group (P<0.05).The ratios of TSLPR +and OX40L+cells did not differ among dif-ferent concentrations of Ag 85B groups.The ratios of TSLPR +and OX40L+cells were significantly increased in 100 μg/L and 200μg/L TSLP groups compared with control group and 50μg/L TSLP group (P<0.05).Under the circumstance of optimal Ag85B or TSLP treatment concentration at 200 μg/L, there was significantly decreased in TSLPR and OX 40L cell ratio of mDCs in Ag85B group or Ag85B combined with TSLP group when compared with TSLP group (P<0.05), and no significant difference among Ag85B group, Ag85B combined with TSLP group and control group was observed .CONCLU-SION: Ag85B enhances mDCs maturation by up-regulating the expression of co-stimulatory molecules CD80 and CD86, and inhibit the expression of pro-inflammatory specific molecules TSLPR and OX40L on TSLP-activated mDCs, indicating that Ag85B modifies the development of asthmatic airway inflammation through the pathway of TSLP -activated mDCs.

Ox-LDL increases OX40L in endothelial cells through a LOX-1-dependent mechanism

Oxidative low-density lipoprotein (Ox-LDL) is a key risk factor for the development of atherosclerosis, and it can stimulate the expression of a variety of inflammatory signals. As a new and highly sensitive inflammation index, OX40L may be a key to understanding the mechanisms that regulate interactions between cells within the vessel wall and inflammatory mediators during the development of atherosclerosis. To investigate whether Ox-LDL regulates OX40L expression through an oxidized LDL-1 receptor (LOX-1)-mediated mechanism, we investigated the effect of different concentrations of Ox-LDL (50, 100, 150 µg/mL) on endothelial cell proliferation and apoptosis. Stimulation with Ox-LDL increased OX40L protein 1.44-fold and mRNA 4.0-fold in endothelial cells, and these effects were inhibited by blocking LOX-1. These results indicate that LOX-1 plays an important role in the chronic inflammatory process in blood vessel walls. Inhibiting LOX-1 may reduce blood vessel inflammation and provide a therapeutic option to limit atherosclerosis progression.

Heterogeneity of IL-22-producing Lymphoid Tissue Inducer-like Cells in Human and Mouse

Lymphoid tissue inducer (LTi) cells have been characterized in mouse as a key cell when secondary lymphoid tissues are organized during development and memory T cells are formed after birth. In addition to their involvement in adaptive immune responses, recent studies show that they contribute to innate immune responses by producing large amount of interleukin (IL)-22 against microbial attack. Here, we compare IL-22-producing LTi and LTi-like cells in human and mouse and discuss their heterogeneity in different tissues.

Effect of anti-CD134 mAb or CTLA4Ig on secretion of IL-6,IFN-? and production of anti-dsDNA antibody from lupus-prone BXSB mice in vitro / 中国免疫学杂志

Objective:To investigate the effect of anti-CD134 mAb or CTLA4Ig on ConA induced splenic cell proliferation,Th cytokine secretion and production of anti-dsDNA antibody from splenic lymphtocyte in vitro in lupus-prone BXSB mice. Methods:Eighteen male lupus-prone BXSB mice model and 6 syngeneic normal C57BL/6 male mice were used in the experiment. The model mice were divided into three groups:un-treated group,Lupus recipe(LR) treated group and prednisone(pred. ) treated group. The mice's splenic cell suspension from above groups was culture stimulated by ConA respectively. The splenic cells from un-treated model mice were further divided into Anti-GD134L mAb,CTLA4Ig or Anti-CD134L mAb + CTLA4Ig treated subgroups. The ConA induced splenic cell proliferation was measured by MTT colorimetric assay. The levels of IFN-?, IL-6 and anti-dsDNA antibody in cell supernatant were measured by ELISA. Results; (1 )The splenic cell proliferative reaction and contents of IFN-?,IL-6 and anti-dsDNA antibody in cell supernatant of either spontaneous or ConA induced culture in the un-treated model group were obviously higher than that of the normal control or other groups. (2) The splenic cell proliferative reaction and production of IFN-?,IL-6 and anti-dsDNA antibody in the CD134L/CTLA4Ig treated group,LR treated goup or pred. treated group was not different from the normal control significantly. (3)To compared with CD134L treated group or CTLA4Ig treated gruop,the CD134L/CTLA4Ig and prednisone reduced significantly the splenic cell proliferative reaction and production of IFN-?,IL-6 and anti-dsDNA antibody in cell supernatant of either spontaneous or ConA induced culture,while no difference was found between CD134L treated group and CTLA4Ig treated proup. Conclusion:The lupus-prone BXSB mice might present abnormal lymphocyte proliferation,spontaneously express cytokines and secrete high level of autoantibody during the SLE development. LR and corticosteroids could obviously inhibit the abnormal lymphocyte proliferation;reduce the Th cytokine formation and antoantibody production Blockade of CD134-CD134L or B7-CD28 costimulatory pathway by Anti-CD134L rnAb or CT-LA4Ig could inhibit the activation of T cells and B cells like LR and corticosteroids. Furthermore, by blockade of both CD134-CD134L and CD28-B7 pathways,the frequency of alloreactive T cell was markedly reduced and was maintained at low levels so as to treat SLE effectively.