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

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 / agonistic antibody / OX40L noncompetitive

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Acknowledgements

We gratefully acknowledge the beamline staff members at BL17U1 of the Shanghai Synchrotron Radiation Facility (SSRF) and Yi Han from the X-ray Crystallography Platform of the Institute of Biophysics for their technical support with diffraction data collection.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-0996-8 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest 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, and Ye Liu have ownership interest in BeiGene.

All procedures involving primary human T cells, DCs and PBMCs were reviewed and approved by the Institutional Review Board (IRB) at BeiGene. All experiments involving animals were approved by the Animal Care and Use Committee of BeiGene according to the guidelines of the Chinese Association for Laboratory Animal Sciences (BeiGene IACUC; IACUC No. 2019123)

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