BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models.
- Author:
Beibei JIANG
1
;
Tong ZHANG
1
;
Minjuan DENG
2
;
Wei JIN
2
;
Yuan HONG
1
;
Xiaotong CHEN
1
;
Xin CHEN
1
;
Jing WANG
1
;
Hongjia HOU
1
;
Yajuan GAO
1
;
Wenfeng GONG
1
;
Xing WANG
1
;
Haiying LI
1
;
Xiaosui ZHOU
1
;
Yingcai FENG
1
;
Bo ZHANG
1
;
Bin JIANG
2
;
Xueping LU
2
;
Lijie ZHANG
2
;
Yang LI
2
;
Weiwei SONG
2
;
Hanzi SUN
1
;
Zuobai WANG
3
;
Xiaomin SONG
1
;
Zhirong SHEN
2
;
Xuesong LIU
1
;
Kang LI
4
;
Lai WANG
1
;
Ye LIU
5
Author Information
- Publication Type:Journal Article
- Keywords: BGB-A445; OX40; OX40L noncompetitive; agonistic antibody
- MeSH: Mice; Animals; Receptors, Tumor Necrosis Factor/physiology*; Receptors, OX40; Membrane Glycoproteins; Ligands; Antibodies, Monoclonal/pharmacology*; Antineoplastic Agents/pharmacology*
- From: Frontiers of Medicine 2023;17(6):1170-1185
- CountryChina
- Language:English
- 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.
