t 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 an...t 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.展开更多
Fritillaria thunbergii Miq. has been widely used in traditional Chinese medicine for its expectorant, antitussive, antiinflammatory and analgesic properties. Moreover, modern pharmacological studies have demonstrated ...Fritillaria thunbergii Miq. has been widely used in traditional Chinese medicine for its expectorant, antitussive, antiinflammatory and analgesic properties. Moreover, modern pharmacological studies have demonstrated that F. thunbergii Miq. has efficacy in the treatment of leukemia and cancers of the liver and cervix. Although the alkaloid, peimine, is largely responsible for these pharmacological effects, it has very low oral bioavailability. The aim of this study was to investigate the intestinal absorption of peimine in Caco-2 cell monolayers. Having demonstrated that peimine is non-toxic to Caco-2 cells at concentrations o200 μmol/L, the effect of peimine concentration, p H, temperature, efflux transport protein inhibitors and EDTA-Na_2 on peimine transport were studied. The results show that peimine transport is concentration-dependent; that at p H 6.0 and 7.4, the P_(app(AP-BL))of peimine is not significantly different but the Papp(BL-AP)) is; that both Papp(AP-BL)and P_(app(BL-AP))at 4 1C are significantly higher than their corresponding values at 37 1C; that the P-glycoprotein(P-gp) inhibitors, verapamil and cyclosporin A, increase absorption of peimine; and that EDTA-Na2 has no discernible effect. In summary,the results demonstrate that the intestinal absorption of peimine across Caco-2 cell monolayers involves active transport and that peimine is a substrate of P-gp.展开更多
文摘t 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.
基金supported by a grant from the Natural Science Foundation of Jiangxi Province (Grant No. 2008GZY0115)financially supported by the National Natural Science Foundation of China (Grant No. 81060346)
文摘Fritillaria thunbergii Miq. has been widely used in traditional Chinese medicine for its expectorant, antitussive, antiinflammatory and analgesic properties. Moreover, modern pharmacological studies have demonstrated that F. thunbergii Miq. has efficacy in the treatment of leukemia and cancers of the liver and cervix. Although the alkaloid, peimine, is largely responsible for these pharmacological effects, it has very low oral bioavailability. The aim of this study was to investigate the intestinal absorption of peimine in Caco-2 cell monolayers. Having demonstrated that peimine is non-toxic to Caco-2 cells at concentrations o200 μmol/L, the effect of peimine concentration, p H, temperature, efflux transport protein inhibitors and EDTA-Na_2 on peimine transport were studied. The results show that peimine transport is concentration-dependent; that at p H 6.0 and 7.4, the P_(app(AP-BL))of peimine is not significantly different but the Papp(BL-AP)) is; that both Papp(AP-BL)and P_(app(BL-AP))at 4 1C are significantly higher than their corresponding values at 37 1C; that the P-glycoprotein(P-gp) inhibitors, verapamil and cyclosporin A, increase absorption of peimine; and that EDTA-Na2 has no discernible effect. In summary,the results demonstrate that the intestinal absorption of peimine across Caco-2 cell monolayers involves active transport and that peimine is a substrate of P-gp.
