1.BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models.
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
Frontiers of Medicine 2023;17(6):1170-1185
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.
Mice
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Animals
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Receptors, Tumor Necrosis Factor/physiology*
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Receptors, OX40
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Membrane Glycoproteins
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Ligands
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Antibodies, Monoclonal/pharmacology*
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Antineoplastic Agents/pharmacology*
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