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.

The proliferation inhibition of colon cancer cells by agonistic CD40 monoclonal antibody in vitro / 国际生物医学工程杂志

Objective To investigate the inhibitory effect of agonistic CD40 monoclonal antibody on the colon cancer cells (HCT116) proliferation in vitro.Methods The DCs (dendritic cells) loaded with tumor cells (HCT116) antigens were activated by different methods.According to the activation method,the cells were divided into three groups:agonistic CD40 monoclonal antibody group,blank control group and TNF-α positive control group.The cells were cultured for 7 days,and the expression rates of CD80,CD83,CD86 and HLA-DR on DC surface in each group were detected by flow cytometry.The concentration of cytokine IL-12(p70) in DCs culture supernatant was determined by ELISA kit.The proliferation activity of the T lymphocytes was evaluated by MTT (methyl thiazolyl tetrazolium).Then the inhibition rate of colon cancer HCT116 cells proliferation,which induced by the tumor-specific effector T lymphocytes,was assayed.Results Compared with the blank control group,the agonistic CD40 monoclonal antibody group had a significantly higher expression rates of CD80,CD83,CD86 and HLA-DR on DC surface (P＜0.05).The concentration of IL-12 in the supernatant of DC was also much higher in the agonistic CD40 monoclonal antibody group (P＜0.05,(716.80±53.43) pg/ml vs.(405.51 ±12.17) pg/ml).The DCs activated by CD40 monoclonal antibody had stronger ability to stimulate proliferation of T lymphocytes (P＜0.05,the stimulation index was (2.006 2±0.438 3) to (1.365 0±0.209 8)).The tumor-specific CTLs induced by DCs in the agonistic CD40 monoclonal antibody group had stronger ability to inhibit colon cancer HCT116 cells (P＜0.05,the inhibition rate was (66.08±0.41)％ vs.(46.60± 1.10)％).However,there was no statistical significance between the agonistic CD40 monoclonal antibody group and the TNF-α positive control group (P＞0.05).Conclusion Agonistic CD40 monoclonal antibody in vitro can promote activation and mature of DCs,then the activated DCs can induce the production of tumor-specific CTL,which can significantly inhibit the proliferation of colon cancer HCT116 cells.