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

IF 3.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Frontiers of Medicine Pub Date : 2023-12-01 Epub Date: 2023-09-25 DOI:10.1007/s11684-023-0996-8
Beibei Jiang, Tong Zhang, Minjuan Deng, Wei Jin, Yuan Hong, Xiaotong Chen, Xin Chen, Jing Wang, Hongjia Hou, Yajuan Gao, Wenfeng Gong, Xing Wang, Haiying Li, Xiaosui Zhou, Yingcai Feng, Bo Zhang, Bin Jiang, Xueping Lu, Lijie Zhang, Yang Li, Weiwei Song, Hanzi Sun, Zuobai Wang, Xiaomin Song, Zhirong Shen, Xuesong Liu, Kang Li, Lai Wang, Ye Liu
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Abstract

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.

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BGB-A445是一种新型的非配体阻断激动性抗OX40抗体,在临床前模型中表现出优异的免疫激活和抗肿瘤作用。
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、分化和活化,还促进树突细胞成熟以增强其细胞因子的产生。因此,激动性抗OX40抗体在癌症免疫治疗中的应用引起了人们的极大兴趣。然而,临床上大多数激动性抗OX40抗体都是OX40L竞争性的,并且显示出有限的疗效。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,在不损害树突状细胞功能的情况下诱导了最佳的T细胞活化。此外,BGB-A445通过抗体依赖性细胞毒性在体外和体内剂量依赖性且显著耗竭调节性T细胞。在人源化OX40敲除小鼠中建立的MC38同基因模型中,BGB-A445表现出强大的剂量依赖性抗肿瘤功效,而配体竞争性抗OX40抗体表现出以钩效应为特征的抗肿瘤功效。此外,BGB-A445与抗PD-1抗体显示出强烈的联合抗肿瘤作用。总之,我们的研究结果表明,与临床阶段的抗OX40抗体相比,BGB-A445不阻断OX40-OX40L相互作用,显示出优越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。
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来源期刊
Frontiers of Medicine
Frontiers of Medicine ONCOLOGYMEDICINE, RESEARCH & EXPERIMENTAL&-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
18.30
自引率
0.00%
发文量
800
期刊介绍: Frontiers of Medicine is an international general medical journal sponsored by the Ministry of Education of China. The journal is jointly published by the Higher Education Press and Springer. Since the first issue of 2010, this journal has been indexed in PubMed/MEDLINE. Frontiers of Medicine is dedicated to publishing original research and review articles on the latest advances in clinical and basic medicine with a focus on epidemiology, traditional Chinese medicine, translational research, healthcare, public health and health policies.
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