8JEL

Crystal structure of TIGIT in complexed with Ociperlimab, crystal form I

8JEL の概要

• エントリーDOI: 10.2210/pdb8jel/pdb
• 分子名称: antibody heavy chain, antibody light chain, T-cell immunoreceptor with Ig and ITIM domains, ... (4 entities in total)
• 機能のキーワード: immunotherapy, antibody, checkpoint inhibitor, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 239386.83

構造登録者

Sun, J.,Zhang, X.X.,Song, J. (登録日: 2023-05-16, 公開日: 2024-02-28, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.45 Å)