In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2628-2628
Abstract:
Background: Tim-3 (T-cell immunoglobin and mucin-domian containing-3) is a “checkpoint” inhibitory receptor, which is primarily expressed in activated or “exhausted” T cells, NK cells, macrophages and DCs. Engagement of Tim-3 receptor by its ligand phosphatidylserine (PtdSer) or galectin-9 leads to activation of negative regulatory signaling in T-cells, promoting functional exhaustion of tumor-infiltrating T-lymphocytes. BGB-A425 is a novel humanized IgG1 (variant) anti-Tim-3 antibody under preclinical development. The immunomodulatory activity of BGB-A425 was evaluated both in vitro and in vivo. Materials and methods: BGB-A425 was generated through hybridoma fusion, humanized by CDR grafting and structural simulation. The Fc region (IgG1) of BGB-A425 was engineered to remove Fc gamma receptor (FcγR) binding. The binding affinity and specificity were studied by ELISA, FACS and SPR (Biacore). The immunomodulatory functions of BGB-A425 were evaluated using primary immune cells as well as cell lines. Results: BGB-A425 binds to the extracellular domain of human Tim-3 with high affinity (KD = 0.36 nM) and specificity. In a competition assay, BGB-A425 efficiently blocks the interactions between Tim-3 and PtdSer. In vitro, BGB-A425 significantly enhances IFN-γ production of primary T cells and NK-mediated cytotoxicity against tumor cells. In a MLR assay, BGB-A425 augments T-cell response to allogeneic antigens either alone or in combination with an anti-PD-1 antibody BGB-A317. Besides blocking Tim-3, BGB-A425 can also induce the internalization of Tim-3 receptor on cell surface. In vivo, BGB-A425 in combination with BGB-A317 inhibits tumor growth in a mouse xenograft cancer model. Conclusions: BGB-A425 demonstrates potent activity to stimulate immune cell function both in vitro and in vivo, supporting its clinical development for the treatment of human cancers. Citation Format: Tong Zhang, Liu Xue, Jing Zhang, Qi Liu, Jie Ma, Yi Zhang, Yingdi Shi, Hongjia Hou, Hao Peng, Ning Liu, Yilu Zhang, Xiaomin Song, Yucheng Li, Jing Song, Lai Wang, Min Wei, Kang Li. BGB-A425: a humanized anti-human Tim-3 antibody that exhibits strong immune cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2628. doi:10.1158/1538-7445.AM2017-2628
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-2628
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
