OX40 是一种共刺激受体，主要在活化的 CD4、CD8 和调节性 T 细胞上表达。 OX40与其唯一配体OX40L的连接增强了T细胞的扩增、分化和激活，还促进树突状细胞成熟以增强其细胞因子的产生。因此，使用激动性抗OX40抗体进行癌症免疫治疗引起了极大的兴趣。然而，临床上大多数激动性抗OX40抗体都具有OX40L竞争性，且疗效有限。在这里，我们发现 BGB-A445（一种目前正在临床研究中的非配体竞争性激动性抗 OX40 抗体）可诱导最佳 T 细胞激活而不损害树突状细胞功能。此外，BGB-A445 通过抗体依赖性细胞毒性，在体外和体内以剂量依赖性方式显着耗尽调节性 T 细胞。在人源化OX40敲入小鼠中建立的MC38同系模型中，BGB-A445表现出强大且剂量依赖性的抗肿瘤功效，而配体竞争性抗OX40抗体则表现出以钩状效应为特征的抗肿瘤功效。此外，BGB-A445 与抗 PD-1 抗体表现出强大的联合抗肿瘤作用。总而言之，我们的研究结果表明，与临床阶段的抗 OX40 抗体相比，BGB-A445 不会阻断 OX40-OX40L 相互作用，显示出优异的免疫刺激作用和抗肿瘤功效，因此值得进一步的临床研究。© 2023。教育出版社。

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.© 2023. Higher Education Press.