Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer

• Published in: mAbs Vol. 15; no. 1; p. 2153409
• Main Authors: Guan, Jiawei, Liu, Hongchuan, Chai, Yan, Yu, Jie, Yao, Jian, Wang, Jing, Pan, Zhiwei, Zhang, Jing, Zhou, Yuehua, Liu, Hui, Yao, Sheng, Qi, Jianxun, Feng, Hui, Gao, George F, Wang, Qihui, Shi, Yi, Tan, Shuguang
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 2023; Taylor & Francis Group
• Subjects: Antibodies, Blocking; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; antibody; Complementarity Determining Regions; CTLA-4; high affinity; Humans; Ipilimumab - pharmacology; Ipilimumab - therapeutic use; JS007; Neoplasms - therapy; structure; high affinity; CTLA-4; antibody; structure; JS007
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2022.2153409

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.