Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer
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...
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Taylor & Francis Group
2023-12-01
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| Serier: | mAbs |
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| Online adgang: | https://www.tandfonline.com/doi/10.1080/19420862.2022.2153409 |
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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 |
| author_facet | 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 |
| author_sort | Jiawei Guan |
| collection | DOAJ |
| description | 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 blockade mAbs and shed light on future development of agents targeting CTLA-4. |
| format | Article |
| id | doaj-art-a7f6d01c43cd47519759b8c736f47447 |
| institution | Matheson Library |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-a7f6d01c43cd47519759b8c736f474472025-07-23T08:11:25ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2022.2153409Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancerJiawei Guan0Hongchuan Liu1Yan Chai2Jie Yu3Jian Yao4Jing Wang5Zhiwei Pan6Jing Zhang7Yuehua Zhou8Hui Liu9Sheng Yao10Jianxun Qi11Hui Feng12George F. Gao13Qihui Wang14Yi Shi15Shuguang Tan16Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), ChinaDepartment of Antibody Discovery and Engineering, Shanghai Junshi Biosciences Co Ltd, Shanghai, ChinaKey Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), ChinaPilot National Laboratory for Marine Science and Technology (Qingdao), Shandong, ChinaDepartment of Antibody Discovery and Engineering, Shanghai Junshi Biosciences Co Ltd, Shanghai, ChinaDepartment of Antibody Discovery and Engineering, Shanghai Junshi Biosciences Co Ltd, Shanghai, ChinaDepartment of Antibody Discovery and Engineering, Shanghai Junshi Biosciences Co Ltd, Shanghai, ChinaDepartment of Antibody Discovery and Engineering, Shanghai Junshi Biosciences Co Ltd, Shanghai, ChinaDepartment of Antibody Discovery and Engineering, Shanghai Junshi Biosciences Co Ltd, Shanghai, ChinaDepartment of Antibody Discovery and Engineering, Shanghai Junshi Biosciences Co Ltd, Shanghai, ChinaDepartment of Antibody Discovery and Engineering, Shanghai Junshi Biosciences Co Ltd, Shanghai, ChinaKey Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), ChinaDepartment of Antibody Discovery and Engineering, Shanghai Junshi Biosciences Co Ltd, Shanghai, ChinaKey Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), ChinaKey Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), ChinaKey Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), ChinaKey Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), ChinaCytotoxic 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 blockade mAbs and shed light on future development of agents targeting CTLA-4.https://www.tandfonline.com/doi/10.1080/19420862.2022.2153409CTLA-4antibodyhigh affinitystructureJS007 |
| spellingShingle | 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 Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer mAbs CTLA-4 antibody high affinity structure JS007 |
| title | Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer |
| title_full | Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer |
| title_fullStr | Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer |
| title_full_unstemmed | Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer |
| title_short | Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer |
| title_sort | characterization of the high affinity anti ctla 4 monoclonal antibody js007 for immune checkpoint therapy of cancer |
| topic | CTLA-4 antibody high affinity structure JS007 |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2022.2153409 |
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