Abstract 5179: Development of a humanized mouse model for direct evaluation of anti-human PD-L1 antibodies

Abstract

Abstract Therapies that perturb the binding of programmed death-1 receptor ligand (PD-L1) to its receptor PD-1 achieved unprecedented rates of sustained clinical responses in patients with various types of cancer. Mouse surrogate antibodies were initially evaluated in syngeneic mouse models as the proof of concept for anti-PD-L1 therapy. However, there's an urgent need to develop appropriate animal model to directly evaluate anti-human PD-L1 antibodies before clinical trial. Here we describe our ongoing efforts in developing a chimeric mouse/human cell line to test human anti PD-L1 antibody. We profiled PD-L1 expression by FACS using anti-mouse PD-L1 antibody and confirmed expression of PD-L1 in a series of murine cancer cell lines. H22, a liver cancer line with moderate expression level of PD-L1 was selected due to its in vivo sensitivity towards anti-PD1 and anti-PD-L1 antibodies. Crispr/cas9 system was employed to knockout murine PD-L1 and replace it with the human counterpart. The targeted knockout had been confirmed by sequencing, the expression of human PD-L1 is illustrated by FACS using antibody that specifically recognize human form and no cross reaction to mouse form. The engineered H22-hPD-L1 cell line was then inoculated subcutaneously to immune-competent BALB/c mice to establish the in vivo model that maintains complete murine immune system and harbor humanized PD-L1. The tumor growth curve of H22-hPD-L1 model and its sensitivity to anti-human PD-L1 antibody have been established. In summary, our H22-hPD-L1 model may be a valuable tool to evaluate the in vivo activity of anti-human PD-L1 antibody therapies either as a single agent or combinational strategies. The similar engineering may be applied to more murine cell lines (e.g. EMT-6, B16F10 and MBT-2, etc) to provide a spectrum of cell lines with different diseases and genetic makeup for immunotherapies involving anti-hPD-L1 antibodies. Citation Format: Meng Qiao, Juan Zhang, Jian Ding, Rui Zhang, Zhongliang Li, Jia Zheng, Teng Lu, Jinjing Ning, Qian Shi. Development of a humanized mouse model for direct evaluation of anti-human PD-L1 antibodies. [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 5179.