Abstract 5002: Anti-tumor activity of a novel anti-human PD-1 antibody BGB-A317 in mouse models
Authors: Xiaomin Song, Zhiyu Tang, Tong Zhang, Mingming Guo, Wenfeng Gong, Yong Liu, Ningning Zhang, Yilu Zhang, Yanjuan Zhang, Jie Ma, Jing Song, Kang Li, Lai Wang
Journal: Cancer Research (2016)

Abstract Background: Programmed death receptor-1 (PD-1) is a co-inhibitory immune checkpoint molecule. The engagement of PD-1 by its ligands negatively regulates T cell function and induces immune tolerance in both normal and pathological conditions, especially in cancer. BGB-A317 is a novel humanized IgG4 anti-PD-1 antibody under clinical development. The anti-tumor activity of BGB-A317 was evaluated in mouse models and reported here. Material and methods: NOD/SCID mice transplanted with human peripheral blood monocyte (PBL-SCID models) were employed to examine the anti-tumor activity and pharmacokinetics of BGB-A317. In these models, human PBMCs (4-5×106) from healthy donors were co-injected with human tumor cells (A431, 2.5×106) or primary tumor tissue fragments derived from cancer patients (BCCO-028 and BCLU-054, 3×3×3 mm3) subcutaneously in the right flank of the mice. BCCO-028 is human colon cancer and BCLU-054 is human non-small cell lung cancer (NSCLC). The mice were then treated with BGB-A317 or PBS intra-peritoneally once a week from the day of tumor implantation. The tumor infiltrated lymphocytes and PD-L1 expression were examined by immunohistochemistry staining and flow cytometry. Results: In A431 model, 3 doses of BGB-A317, 1, 3, 10mg/kg, were examined. All three doses of BGB-A317 induced significant tumor growth inhibition (TGI) on day 29 (78%, 89%, and 89%, respectively) (p &amp;lt; 0.001 vs. vehicle treatment). Both AUC0-168h and Cmax of BGB-A317 after single dose (day 1, 1st dose) or at steady state (day 29, 5th dose) increased proportionally from 1 to 10 mg/kg. There was about 2-fold accumulation in drug levels (AUC0-168h and Cmax) at the steady state compared to those after single dose. Increased lymphocyte infiltration and PD-L1 expression were observed in BGB-A317 treated groups. In BCCO-028 model, BGB-A317 at 10 mg/kg QW induced significant tumor growth inhibition, with 83% TGI (p &amp;lt; 0.05 vs. vehicle treatment) on day 36. In BCLU-054 model, BGB-A317 at 10 mg/kg QW induced significant tumor growth inhibition, with 45% of TGI (p &amp;lt; 0.05 vs. vehicle treatment) on day 23. BGB-A317 treatment had no significant impact on animal body weight throughout all of the studies. Conclusions: BGB-A317 demonstrated significant anti-tumor activity in 3 human cancer xenograft PBL-SCID mouse models, including A431 human epidermoid carcinoma, BCCO-028 colon cancer, and BCLU-054 NSCLC models. Citation Format: Xiaomin Song, Zhiyu Tang, Tong Zhang, Mingming Guo, Wenfeng Gong, Yong Liu, Ningning Zhang, Yilu Zhang, Yanjuan Zhang, Jie Ma, Jing Song, Kang Li, Lai Wang. Anti-tumor activity of a novel anti-human PD-1 antibody BGB-A317 in mouse models. [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 5002.