8HIT

Crystal structure of anti-CTLA-4 humanized IgG1 MAb--JS007 in complex with human CTLA-4

Summary for 8HIT

• Entry DOI: 10.2210/pdb8hit/pdb
• Descriptor: JS007-VH, JS007-VL, Cytotoxic T-lymphocyte protein 4 (3 entities in total)
• Functional Keywords: complex, anti-body, scfv, immune system
• Biological source: Mus musculus; More
• Total number of polymer chains: 3
• Total formula weight: 37671.14

Authors

Tan, S.,Shi, Y.,Wang, Q.,Gao, G.F.,Guan, J.,Chai, Y.,Qi, J. (deposition date: 2022-11-21, release date: 2023-02-01, Last modification date: 2024-10-16)

Primary citation

Guan, J.,Liu, H.,Chai, Y.,Yu, J.,Yao, J.,Wang, J.,Pan, Z.,Zhang, J.,Zhou, Y.,Liu, H.,Yao, S.,Qi, J.,Feng, H.,Gao, G.F.,Wang, Q.,Shi, Y.,Tan, S.
Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer.
Mabs, 15:2153409-2153409, 2023

PubMed Abstract: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical inhibitory checkpoint molecule, and monoclonal antibodies (mAbs) targeting CTLA-4 that restore anti-tumor T cell immunity have achieved clinical success. Here, we report a humanized IgG1 mAb, namely JS007, with high binding affinity to CTLA-4. JS007 shows superior binding affinity and T-cell activating efficiency over ipilimumab. Moreover, it demonstrates substantial tumor suppression efficacy at low doses. The crystal structure of JS007/CTLA-4 complex (PDB: 8HIT) shows JS007 adopts a heavy-chain-dominant binding mode, and mainly contacts the BC loop, DE loop and FG loop of CTLA-4. Notably, two Tyr residues (VH-Y100 and VL-Y32) from the complementarity-determining region loops insert into the two cavities formed by the residues from the loops of CTLA-4, which may contribute to the stabilization of the binding. Comparative analysis with other anti-CTLA-4 mAbs indicates that the double "wedge-into-hole" binding mode is unique for JS007 and may be responsible for the high-affinity binding to CTLA-4. These findings have provided an important molecular understanding of the high-affinity CTLA-4 blockade mAbs and shed light on future development of agents targeting CTLA-4.

PubMed: 36511654
DOI: 10.1080/19420862.2022.2153409

Experimental method

X-RAY DIFFRACTION (3.2 Å)