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Crystal structure of TIGIT in complexed with Tiragolumab
Structural highlights
FunctionTIGIT_HUMAN Binds with high affinity to the poliovirus receptor (PVR) which causes increased secretion of IL10 and decreased secretion of IL12B and suppresses T-cell activation by promoting the generation of mature immunoregulatory dendritic cells. Publication Abstract from PubMedTIGIT is mainly expressed on T cells and is an inhibitory checkpoint receptor that binds to its ligand PVR in the tumor microenvironment. Anti-TIGIT monoclonal antibodies (mAbs) such as Ociperlimab and Tiragolumab block the TIGIT-PVR interaction and are in clinical development. However, the molecular blockade mechanism of these mAbs remains elusive. Here, we report the crystal structures of TIGIT in complex with Ociperlimab_Fab and Tiragolumab_Fab revealing that both mAbs bind TIGIT with a large steric clash with PVR. Furthermore, several critical epitopic residues are identified. Interestingly, the binding affinity of Ociperlimab toward TIGIT increases approximately 17-fold when lowering the pH from 7.4 to 6.0. Our structure shows a strong electrostatic interaction between ASP103(HCDR3) and HIS76(TIGIT) explaining the pH-responsive mechanism of Ociperlimab. In contrast, Tiragolumab does not show an acidic pH-dependent binding enhancement. Our results provide valuable information that could help to improve the efficacy of therapeutic antibodies for cancer treatment. Structural insights into the unique pH-responsive characteristics of the anti-TIGIT therapeutic antibody Ociperlimab.,Sun J, Zhang X, Xue L, Cheng L, Zhang J, Chen X, Shen Z, Li K, Wang L, Huang C, Song J Structure. 2024 May 2;32(5):550-561.e5. doi: 10.1016/j.str.2024.02.009. Epub 2024 , Mar 8. PMID:38460520[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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