699 A differentiated anti-OX40 agonist BGB-A445 does not block OX40-OX40L interaction and reveals remarkable anti-tumor efficacy in preclinical models

• Published in: Journal for immunotherapy of cancer 2020-11, Vol.8 (Suppl 3), p.A741-A741
• Main Authors: Liu, Ye, Jiang, Beibei, Zhang, Tong, Wang, Zuobai, Feng, Yingcai, Li, Haiying, Gong, Wenfeng, Wang, Xing, Gao, Yajuan, Zhou, Xiaosui, Zhang, Bo, Hong, Yuan, Wang, Jing, Wang, Zilin, Hou, Hongjia, Sun, Hanzi, Song, Xiaomin, Li, Kang, Liu, Xuesong
• Format: Article
• Language: English
• Subjects: Antibodies; Colorectal cancer; Crystal structure; Flow cytometry; Immunotherapy; Ligands
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2020-SITC2020.0699

BackgroundOX40 is a member of the tumor necrosis factor receptor super family (TNFRSF) primarily expressed on activated CD4+ and CD8+ T cells, as well as natural killer (NK) T and NK cells. It is an immune costimulatory receptor which binds to its ligand OX40L and activates downstream NF-κB pathway to induce immune cell activation, proliferation, and survival.1–3 Current agonistic anti-OX40 antibodies in clinic, which are mostly ligand-competitive antibodies, showed limited clinical responses, mainly at lower doses. Blockade of OX40-OX40L interaction might limit the efficacy of these ligand-competitive antibodies at higher doses, as OX40-OX40L interaction is essential for enhancing effective anti-tumor immunity. Here we report pre-clinical data of BGB-A445, which is a ligand non-blocking agonistic anti-OX40 humanized antibody.MethodsCell-based flow cytometry assay was established to determine whether BGB-A445 interferes with OX40-OX40L interaction. Co-crystal structure of OX40/BGB-A445 Fab was solved to study the molecular binding mechanism. A mixed lymphocyte reaction (MLR) assay was set up to investigate the ability of BGB-A445 to activate CD4+ T-cells. The anti-tumor efficacy of BGB-A445 was evaluated in MC38 colon cancer and CT26WT colon cancer models either as a single agent or in combination with anti-PD-1 antibody.ResultsThe flow cytometry study showed that BGB-A445 did not interfere with the binding of OX40 to OX40L even at high concentrations. In contrast, MOXR0916, an anti-OX40 agonistic antibody developed by Genentech, completely blocked OX40 binding to OX40L. Additionally, the co-crystal structure of OX40/BGB-A445 Fab complex indicated that BGB-A445 interacts with the CRD4 region of OX40 which is distant from OX40L binding region. In the MLR assay, combined with an anti-PD-1 antibody, BGB-A445 co-stimulated CD4+ T-cells to secrete IL-2 dose-dependently, while MOXR0916 did not. In the MC38 colon cancer model in human OX40 knock-in mice, BGB-A445 demonstrated remarkable anti-tumor efficacy in a dose-dependent manner, while MOXR0916 showed a ‘hook effect’ in the same setting. In addition, BGB-A445 exhibited significant anti-tumor activity in the PAN02 pancreatic model which is resistant to anti-PD-1 treatment. Besides, BGB-A445 revealed significant combination effects with anti-PD-1 therapy in both MC38 and CT26WT models.ConclusionsIn conclusion, differentiated from current clinical stage anti-OX40 antibodies, BGB-A445 is an agonistic antibody tha