7law
crystal structure of GITR complex with GITR-L
Structural highlights
FunctionTNF18_HUMAN Cytokine that binds to TNFRSF18/AITR/GITR. Regulates T-cell responses. Can function as costimulator and lower the threshold for T-cell activation and T-cell proliferation. Important for interactions between activated T-lymphocytes and endothelial cells. Mediates activation of NF-kappa-B.[1] [2] Publication Abstract from PubMedCostimulatory 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 FcgammaR-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. An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy.,Chan S, Belmar N, Ho S, Rogers B, Stickler M, Graham M, Lee E, Tran N, Zhang D, Gupta P, Sho M, MacDonough T, Woolley A, Kim H, Zhang H, Liu W, Zheng P, Dezso Z, Halliwill K, Ceccarelli M, Rhodes S, Thakur A, Forsyth CM, Xiong M, Tan SS, Iyer R, Lake M, Digiammarino E, Zhou L, Bigelow L, Longenecker K, Judge RA, Liu C, Trumble M, Remis JP, Fox M, Cairns B, Akamatsu Y, Hollenbaugh D, Harding F, Alvarez HM Nat Cancer. 2022 Mar;3(3):337-354. doi: 10.1038/s43018-022-00334-9. Epub 2022 Mar , 7. PMID:35256819[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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