8JEO

Crystal structure of TIGIT in complexed with Tiragolumab

Summary for 8JEO

• Entry DOI: 10.2210/pdb8jeo/pdb
• Descriptor: T-cell immunoreceptor with Ig and ITIM domains, antibody heavy chain, antibody light chain, ... (4 entities in total)
• Functional Keywords: immunotherapy, antibody, checkpoint inhibitor, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 124832.78

Authors

Sun, J.,Zhang, X.X.,Song, J. (deposition date: 2023-05-16, release date: 2024-02-28, Last modification date: 2024-11-06)

Primary citation

Sun, J.,Zhang, X.,Xue, L.,Cheng, L.,Zhang, J.,Chen, X.,Shen, Z.,Li, K.,Wang, L.,Huang, C.,Song, J.
Structural insights into the unique pH-responsive characteristics of the anti-TIGIT therapeutic antibody Ociperlimab.
Structure, 32:550-, 2024

PubMed Abstract: TIGIT 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 and HIS76 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.

PubMed: 38460520
DOI: 10.1016/j.str.2024.02.009

Experimental method

X-RAY DIFFRACTION (2.06 Å)