1. An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy.
- Author
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Chan, Sarah, Belmar, Nicole, Ho, Sun, Rogers, Bryan, Stickler, Marcia, Graham, Michelle, Lee, Eileen, Tran, Ninian, Zhang, Dong, Gupta, Priyanka, Sho, Mien, MacDonough, Tracy, Woolley, Andrew, Kim, Han, Zhang, Hong, Liu, Wei, Zheng, Pingping, Dezso, Zoltan, Halliwill, Kyle, Ceccarelli, Michele, Rhodes, Susan, Thakur, Archana, Forsyth, Charles, Xiong, Mengli, Tan, Siu, Iyer, Ramesh, Lake, Marc, Digiammarino, Enrico, Zhou, Li, Bigelow, Lance, Longenecker, Kenton, Judge, Russell, Liu, Cassie, Trumble, Max, Remis, Jonathan, Fox, Melvin, Cairns, Belinda, Akamatsu, Yoshiko, Hollenbaugh, Diane, Harding, Fiona, and Alvarez, Hamsell
- Subjects
Animals ,Cluster Analysis ,Disease Models ,Animal ,Glucocorticoid-Induced TNFR-Related Protein ,Humans ,Immunotherapy ,Mice ,Neoplasms ,Programmed Cell Death 1 Receptor ,Receptors ,Tumor Necrosis Factor ,T-Lymphocytes - Abstract
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 FcγR-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.
- Published
- 2022