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Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer by Jiawei Guan; Hongchuan Liu; Yan Chai; Jie Yu; Jian Yao; Jing Wang; Zhiwei Pan; Jing Zhang; Yuehua Zhou; Hui Liu; Sheng Yao; Jianxun Qi; Hui Feng; George F. Gao; Qihui Wang; Yi Shi; Shuguang Tan is a Medicine article available to read on EtoBox.
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## 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 __in vivo__ 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 blo
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- Author
- Jiawei Guan; Hongchuan Liu; Yan Chai; Jie Yu; Jian Yao; Jing Wang; Zhiwei Pan; Jing Zhang; Yuehua Zhou; Hui Liu; Sheng Yao; Jianxun Qi; Hui Feng; George F. Gao; Qihui Wang; Yi Shi; Shuguang Tan
- Publisher
- Informa UK Limited
- Published
- 2022
- Language
- EN
- Field
- Medicine (Life Sciences)