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

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

  • Front Med. 2023 Dec;17(6):1170-1185. doi: 10.1007/s11684-023-0996-8.
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
Affiliations

Affiliations

  • 1 Department of Biology, BeiGene (Beijing) Co., Ltd., Beijing, 102206, China.
  • 2 Department of Discovery Biomarkers, BeiGene (Beijing) Co., Ltd., Beijing, 102206, China.
  • 3 Department of Clinic Development, BeiGene (Beijing) Co., Ltd., Beijing, 102206, China.
  • 4 Department of Biologics, BeiGene (Beijing) Co., Ltd., Beijing, 102206, China.
  • 5 Department of Biology, BeiGene (Beijing) Co., Ltd., Beijing, 102206, China. ye.liu@beigene.com.
PMID: 37747585 DOI: 10.1007/s11684-023-0996-8
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.

Keywords

BGB-A445; OX40; OX40L noncompetitive; agonistic antibody.

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