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

doi:10.1007/s11684-023-0996-8

2023, Vol. 17

Issue (6) : 1170-1185 https://doi.org/10.1007/s11684-023-0996-8

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

Beibei Jiang¹, Tong Zhang¹, Minjuan Deng², Wei Jin², Yuan Hong¹, Xiaotong Chen¹, Xin Chen¹, Jing Wang¹, Hongjia Hou¹, Yajuan Gao¹, Wenfeng Gong¹, Xing Wang¹, Haiying Li¹, Xiaosui Zhou¹, Yingcai Feng¹, Bo Zhang¹, Bin Jiang², Xueping Lu², Lijie Zhang², Yang Li², Weiwei Song², Hanzi Sun¹, Zuobai Wang³, Xiaomin Song¹, Zhirong Shen², Xuesong Liu¹, Kang Li⁴, Lai Wang¹, Ye Liu¹(

)

¹. Department of Biology
². Department of Discovery Biomarkers
³. Department of Clinic Development
⁴. Department of Biologics, BeiGene (Beijing) Co., Ltd., Beijing 102206, China

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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.

Keywords BGB-A445 OX40 agonistic antibody OX40L noncompetitive

Corresponding Author(s): Ye Liu

Just Accepted Date: 28 July 2023 Online First Date: 26 September 2023 Issue Date: 06 February 2024

Cite this article:

Beibei Jiang,Tong Zhang,Minjuan Deng, et al. BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models[J]. Front. Med., 2023, 17(6): 1170-1185.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0996-8
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I6/1170

Fig.1 BGB-A445 binds to OX40 potently without interfering with OX40–OX40L interaction. (A) Schematic overview of the discovery of BGB-A445. First, antibody clones were generated via hybridoma fusion with splenocytes from OX40 extracellular domain-immunized BALB/c mice. Then, OX40 binding, T cell costimulation, and OX40L-competition assays were performed by using ELISA, SPR, or cell-based assays, respectively. Finally, hit 445 was humanized and optimized to reduce immunogenicity and improve stability. (B) Binding of BGB-A445 to cell-surface-overexpressed OX40 on HuT78 cells determined via FACS. MOXR0916 was used as a reference antibody. (C) Binding of BGB-A445 to cell-surface-expressed OX40 on human primary CD4⁺ T cells from six different donors. In consideration of donor variation, the binding signal was further normalized to the receptor occupancy rate of the OX40 receptor. (D) Non-OX40L-competitive property of BGB-A445 in the cell-based assay and comparison with the properties of other clinical-stage agonistic anti-OX40 antibodies. In this assay, the control was set as OX40 alone, and the experimental groups included OX40 in the presence of huIgG, BGB-A445, or reference antibodies. In (B–D) the data are presented as the mean value ± SD from two (B, C) or three (D) replicates.

Fig.2 Crystal structure of the OX40/BGB-A445 Fab complex further confirms the noncompetitiveness of BGB-A445 with OX40L. (A) Crystal structure of OX40 in complex with BGB-A445 Fab. BGB-A445 is shown as a ribbon (heavy chain, cyan; light chain, light cyan). OX40 is shown as a surface representation. HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of BGB-A445 are highlighted in red, yellow, light golden, pink, blue, and magenta, respectively, and CRD4 of OX40 is colored dark gray. (B) Detailed interactions between BGB-A445 and its key epitopes. BGB-A445 is shown as a gray ribbon and surface, and OX40 is shown as a green ribbon. Key residues are represented as sticks. VDW, van der Waals interaction. (C) Structural alignment of OX40/BGB-A445 Fab with the reported OX40/MOXR0916 (PDB: 6OKN) and OX40/OX40L (PDB: 2HEV) complexes. BGB-A445, MOXR0916, and OX40L are shown as cyan, magenta, and orange ribbons, respectively. Meanwhile, the CRD1–CRD4 regions of OX40 are differentiated with light and dark gray surface representations. (D) Comparison of binding interfaces among BGB-A445, MOXR0916, and OX40L on the OX40 surface. The surfaces colored cyan, magenta, and orange are the binding surfaces of BGB-A445, MOXR0916, and the OX40L trimer, respectively, and the surface colored red represents the overlapping interface of MOXR0916 and the OX40L trimer.

Fig.3 BGB-A445 induces optimal T cell activation and DC maturation. (A) BGB-A445 enhances IL-2 production in conjunction with T cell receptor signaling. HuT78/OX40 cells were cocultured overnight with HEK293/ FcγRI/anti-CD3 cells in the presence of serially diluted OX40 mAbs (BGB-A445 or MOXR0916). IL-2 production in the supernatant was determined by ELISA. (B) Schematic of the CD4⁺ T/DC coculture system. Immature DCs were cocultured with autologous CD4⁺ T cells with SEB and OX40 mAbs for 48 h. The secretion of IL-2 by T cells (C, D) and the expression of costimulatory molecules (CD86 and CD83) on DCs (E) were determined by ELISA and flow cytometry, respectively. (D) Indicated OX40 mAbs (10 μg/mL) were added to the coculture system alone or in combination with OX40L-blocking antibodies (10 μg/mL). The data shown in panels (C) and (D) are representative of at least three independent experiments from multiple donors. The data are presented as mean ± SD (*, P < 0.05).

Fig.4 BGB-A445 dose-dependently increased proliferating and activated Teffs in hOX40 knock-in mice bearing MC38 tumors. hOX40 knock-in mice were inoculated with MC38 cells. Single cells isolated from the spleens were stained and analyzed through flow cytometry at 24 h after the second injection of BGB-A445 or MOXR0916. (A) Number of proliferating (Ki67⁺) CD4 Teffs. (B) Number of proliferating (Ki67⁺) CD8 T cells. (C) Number of proliferating (Ki67⁺) memory CD4 (CD44-high) T cells. (D) Number of proliferating (Ki67⁺) memory CD8 (CD44-high) T cells. All data are presented as mean ± SEM, and each dot represents one mouse sample. Statistically significant differences were analyzed by conducting one-way ANOVA on log-transformed data by using Holm–Sidak’s multiple comparisons test (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001).

Fig.5 BGB-A445 preferentially depletes Tregs and increases the CD8⁺/Treg ratio in vitro and in vivo. (A) In an ADCC assay, NK cells were cocultured with PHA-stimulated PBMCs in the presence of OX40 mAbs (BGB-A445, MOXR0916, or Fc effectorless BGB-A445 mf) overnight. The percentage of Tregs among CD4⁺ cells was determined by flow cytometry, as described in the Methods and Materials section. CD4⁺ effector (B) and CD8⁺ T cell (C) percentages and the CD8⁺/Treg ratio (D) were also determined. (E–G) hOX40 knock-in mice were inoculated with MC38 cells. Tumors were isolated 24 h after the second injection of BGB-A445 or MOXR0916. TILs (CD45⁺ cells) isolated from tumor-dissociated single-cell suspensions were stained and analyzed by flow cytometry. (E) Percentage of Tregs among TILs. (F) Percentage of CD8⁺ T cells among TILs. (G) CD8⁺/Treg ratio. All data are presented as mean ± SEM, and each dot represents one animal. Statistical differences were analyzed by conducting one-way ANOVA on log-transformed data by using Holm–Sidak’s multiple comparisons test (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001).

Fig.6 BGB-A445 executes dose-dependent antitumor activity in MC38 syngeneic tumor models and presents superior efficacy in the PD-1 resistant model PAN02. (A) MC38 tumor cells were implanted s.c. into hOX40 knock-in mice. On day 7 after cell implantation, the mice were randomly allocated into five groups and treated with the vehicle, BGB-A445, or MOXR0916 (0.4, 2, or 10 mpk) i.p. once a week for 2 weeks. The data are presented as mean bodyweight ± SEM for 10 animals in each group. (B) TGI on day 16 was correlated with the dose used in the MC38 model. (C) Animal body weight in the MC38 model group. Statistical differences were analyzed by using nonparametric Dunn’s multiple comparisons test, where * denotes an adjusted P < 0.05, **** denotes an adjusted P < 0.0001, and ns denotes no statistical significance. (D) PAN02 cells were implanted s.c. into hOX40 knock-in mice. The mice were randomly allocated into four groups and treated with the vehicle, BGB-A445, muCh15mt, or MOXR0916 once a week. The data are presented as the mean tumor volume ± SEM from nine animals in each group. The data of the treatment groups were compared with log-transformed data by using Holm–Sidak’s multiple comparisons test (**, P < 0.01; ***, P < 0.001). (E) Body weights of PAN02 model animals.

Fig.7 BGB-A445 exerts a combination effect when used with an anti-PD-1 antibody. (A) BGB-A445 enhances MLR. In vitro-differentiated DCs were cocultured with allogeneic CD4⁺ T cells in the presence of BGB-A445 or MOXR0916 (0.1–10 μg/mL) with or without 50 ng/mL BGB-A317 for 2 days. IL-2 in the supernatant was detected by ELISA. All data are presented as the mean ± SD from quadruplicates. Statistical significance: *, P < 0.05; **, P < 0.01. (B) MC38 tumor cells were implanted s.c. in hOX40 knock-in mice. On day 10 after implantation, the mice were randomly allocated into four groups and treated with the vehicle, BGB-A445 monotherapy, muCh15mt monotherapy, or combination treatment i.p. once a week for 2 weeks. The data are presented as the mean tumor volume ± SEM from nine animals in each group. (C) Tumor volumes in individual animals for the MC38 model. (D) Bodyweights of the MC38 model animals.

Fig.8 Non-OX40L-blocking anti-OX40 antibody may induce superior T cell activation to an OX40L-blocking antibody. BGB-A445 can bind to an OX40 epitope that is different from OX40L and stimulate T cells without impairing APC activation, hence promoting T cell proliferation and activation to maximum levels.

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