The Pd-L1 And Ox40 Bispecific Antibody Ibi327 Induces Immune Activation And Improves Cancer Immunotherapy

Background PD-L1 is a B7 family member which is constantly expressed on anti-tumors, and could be upregulated by INF-γ. OX40, as a member of TNFR superfamily, is expressed primarily on activated T cell. Recent studies highlighted the therapeutic efficacy of PD-L1 and OX40, which utilize the patients9 own immune system to destroy cancerous cell. PD-L1 is known as a negative regulatory molecule, which inhibits T cell function and suppresss anti-tumor immunity. Meanwhile, OX40 as a T cell engager can initiate the T cell activation, and reinvigorate T cell effector function and block Treg suppressive function. PD-L1 blockade antibody and OX40 activating antibody have been shown synergistic effect in tumor regression. To address this mechanism and enhance tumor growth inhibition, we developed PD-L1 and OX40 bispecific antibody (IBI327), which fuses PD-L1 VHH antibody at the C terminal of OX40 antibody IgG2 Fc. By targeting two molecules that are overexpressed in the tumor and activated T cells respectively, there is a potential to increase localization to the tumor area compared to monospecific antibodies. This in turn may reduce the risk of systemic T-cell activation and improve the efficacy. By targeting PD-L1 and OX40 simultaneously, IBI327 is directed to the tumor area where it induces enhanced immune activation and improves cancer immunotherapy. Methods In this study the design a novel bispecific antibody (IBI327), which fuses PD-L1 VHH antibody at the C terminal of OX40 antibody IgG2 Fc. IBI327 bridges hOX40 positive cells with hPD-L1 positive cells and anti-OX40 anti-PD-L1 and IgG were tested in MLR assay and T cells activation assay. The effect of IBI327 on the tumor growth potential Lovo (colon), H292 (lung) and MJ (colon) cell lines was tested. Results Our data shows that IBI327 has high affinity to human PD-L1 and OX40, and anti-PD-L1 shows higher affinity than OX40. Meanwhile, IBI327 retains both PD-L1 and OX40 functions independently. Further, this molecule bridge PD-L1 expressed Tumors or DCs to T cells and activate T effect cell immune function. The vivo studies shows that IBI327 confers a significant tumor regression in humanized model, and induces more CD8 T cell infiltration. Conclusion These results suggest that a PD-L1 OX40 bispecific antibody induces enhanced immune activation and improve cancer immunotherapy. Our study supports that PD-L1 and OX40 bispecific antibody could be a new option for PD-L1 positive or weakly positive patients in clinical. Citation Format: Bingliang Chen, Zhihui Kuang, Yiming Li, Shuaixiang Zhou, Zhihai Wu, Min Wu, Michael Yu, Junjian Liu. The PD-L1 and OX40 bispecific antibody IBI327 induces immune activation and improves cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2268.