7LAW

crystal structure of GITR complex with GITR-L

Summary for 7LAW

• Entry DOI: 10.2210/pdb7law/pdb
• Descriptor: Tumor necrosis factor ligand superfamily member 18, Tumor necrosis factor receptor superfamily member 18, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: gitr-ligand, receptor, complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 61649.56

Authors

Longenecker, K.L.,Rogers, B.,Bigelow, L.,Judge, R.A.,Alvarez, H. (deposition date: 2021-01-07, release date: 2022-03-09, Last modification date: 2024-10-23)

Primary citation

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, C.M.,Xiong, M.,Tan, S.S.,Iyer, R.,Lake, M.,Digiammarino, E.,Zhou, L.,Bigelow, L.,Longenecker, K.,Judge, R.A.,Liu, C.,Trumble, M.,Remis, J.P.,Fox, M.,Cairns, B.,Akamatsu, Y.,Hollenbaugh, D.,Harding, F.,Alvarez, H.M.
An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy.
Nat Cancer, 3:337-354, 2022

PubMed 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 GITRPD-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.

PubMed: 35256819
DOI: 10.1038/s43018-022-00334-9

Experimental method

X-RAY DIFFRACTION (2.752 Å)