Abstract 2226: Anti-human PD-1 antibody BGB-A317 exhibits potent immune cell activation

Abstract

Abstract Background: PD-1 is a “check point” inhibitory receptor, which is primarily expressed in activated and/or exhausted T cells. Engagement of PD-1 receptor by its ligand PD-L1 or PD-L2 (expressed on APCs and some tumor cells), leads to negative regulatory signaling in T-cells, promoting functional exhaustion of tumor-infiltrating T-lymphocytes. BGB-A317 is a novel humanized IgG4 anti-PD-1 antibody under clinical development. The immunomodulatory activity of BGB-A317 was evaluated in in vitro assays and reported here. Materials and methods: BGB-A317 was generated through hybridoma fusion, humanized by CDR grafting and structural simulation. The Fc and hinge regions of BGB-A317 were engineered to remove Fc gamma receptor (FcγR) binding and to stabilize the hinge region. The binding affinity and specificity were studied by ELISA, FACS and SPR (Biacore). The immunomodulatory functions of BGB-A317 were evaluated using both T-cell lines and primary immune cells. Results: BGB-A317 binds to the extracellular domain of human PD-1 with high affinity (KD = 0.15nM) and specificity. In competition assays, BGB-A317 efficiently blocks the interactions between PD-1 and its ligands. In vitro cell-based assays, BGB-A317 significantly enhances cytokine (IL-2 and IFN-γ) production using T-cell line or primary T cells cocultured with signal-sending cells in a dose-dependent manner. BGB-A317 also potently increases NK cell-mediated IFN-γ production and cytotoxicity against PD-L1+ tumor cells. As an important functional attribute, BGB-A317 exhibits no binding to any of FcγRs, including FcγRI, FcγRIIA, FcγRIIB and FcγRIIIA. Therefore, no antibody-dependent cell-mediated (ADCC) or complement-dependent cytotoxicity (CDC) has been observed in activated T cells treated with high concentration of BGB-A317 up to 100 μg/ml. BGB-A317 is stable as bivalent antibody unlike the wild type human IgG4 going through dynamic conformational change, forming bispecific antibody by Fab-arm exchange. Conclusions: BGB-A317 demonstrated potent immune cell activation in in vitro assays, supporting its clinical development for the treatment of human cancers. Keywords: Anti-PD-1, immunotherapy, functional assays Citation Format: Tong Zhang, Jing Song, Yucheng Li, Jie Ma, Yingdi Shi, Xiaoran Wu, Lanlan Xu, Qi Liu, Yanping Cao, Yali Wang, Hao Peng, Hongjia Hou, Xu Zhao, Xiaomin Song, Lai Wang, Min Wei, Lusong Luo, Kang Li. Anti-human PD-1 antibody BGB-A317 exhibits potent immune cell activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2226.