Abstract 1087: Development and characterization of a bispecific antibody (GB265) against PD-L1 and TIGIT

Abstract

Abstract Background: Cancer immunotherapy has transformed cancer therapy. In particular, blockade of the PD-L1/PD-1 axis with PD-1 or PD-L1 antibodies has achieved successful and durable treatment outcomes in some patients across a variety of cancer types. However, primary or acquired resistance to immunotherapy and adverse effects have been observed in cancer patients, due to a hostile TME and the immunosuppressive activity of various inhibitory checkpoint receptors and their ligands on immune cells and cancer cells. It was recently reported that dual blockade of PD-1/PD-L1 and TIGIT/CD155 could improve treatment efficacy in NSCLC patients. We therefore develop bispecific antibody against both PD-L1 and TIGIT with the aim of enhancing the efficacy of therapy and mitigating potential adverse effects. Methods: We obtained TIGIT binders by VHH library panning, and constructed PD-L1/TIGIT BsAbs of two different structures either by fusing the TIGIT VHH to a PD-L1 IgG or by fusing the TIGIT VHH to a PD-L1 VHH-Fc. TIGIT binding and CD155 blocking was analyzed by fluorescence-activated cell sorting (FACS) using Jurkat cells stably expressing TIGIT. Function assays were conducted with a co-culture system of H1975 stably expressing OKT3 and induced human exhausted T cells or luciferase reporter Jurkat cells with high expression of PD-1 and TIGIT. Results: Both bispecific antibodies effectively bind TIGIT on T cells and PD-L1 on PD-L1 positive cancer cells. Interaction between BsAb and the two targets bridge the T cell and the cancer cell and result in the clustering of the antibody-antigen complexes at the contact area of the two cells. Functionally, GB265 antibodies effectively blocked CD155 and PD-1 signal pathways in the cell-based reporter system and exhibited ADCC function specifically to target cancer cells. Conclusion: GB265 antibodies have the potential to outperform PD-L1 and TIGIT monospecific antibodies or their combinations in rejuvenating anti-tumor immunity in cancer patients due to its bridging activity and dual blockade function. Citation Format: Su Huang, Riyao Yang, Cai Huang, Saroja Putrevu, Nathan S. Fay, Kimberly Wright, Mohd Saif Zaman, Betty Huang, Bo Wang, Meredith Wright, Yanan Wang, Xuefei Tian, Yue Liu. Development and characterization of a bispecific antibody (GB265) against PD-L1 and TIGIT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1087.