期刊
NATURE CANCER
卷 3, 期 3, 页码 337-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s43018-022-00334-9
关键词
-
类别
资金
- Industrial Macromolecular Crystallography Association
- Hauptman-Woodward Medical Research Institute
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
This study develops a bispecific anti-PD-1-GITR-L agonist that activates T cells via a mechanism distinct from those found with individual PD-1 and GITR-L agonists and demonstrates its antitumor activity in mice and nonhuman primates.
Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (GITR-L) that induces PD-1-dependent and Fc gamma R-independent GITR clustering, resulting in enhanced activation, proliferation and memory differentiation of primed antigen-specific GITR(+)PD-1(+) T cells. The anti-PD-1-GITR-L bispecific is a PD-1-directed GITR-L construct that demonstrated dose-dependent, immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models, with a dose-dependent correlation between target saturation and Ki67 and TIGIT upregulation on memory T cells. Anti-PD-1-GITR-L thus represents a bispecific approach to directing GITR agonism for cancer immunotherapy. Alvarez and colleagues develop a bispecific anti-PD-1-GITR-L agonist that activates T cells via a mechanism distinct from those found with individual PD-1 and GITR-L agonists and demonstrate its antitumor activity in mice and nonhuman primates.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据