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He M, Chai Y, Qi J, et al. Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies. Oncotarget. 2017;8(40):67129-67139doi: 10.18632/oncotarget.18004.
He, M., Chai, Y., Qi, J., Zhang, C. W. H., Tong, Z., Shi, Y., Yan, J., Tan, S., & Gao, G. F. (2017). Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies. Oncotarget, 8(40), 67129-67139. https://doi.org/10.18632/oncotarget.18004
He, Mengnan, et al. "Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies." Oncotarget vol. 8,40 (2017): 67129-67139. doi: https://doi.org/10.18632/oncotarget.18004
He M, Chai Y, Qi J, Zhang CWH, Tong Z, Shi Y, Yan J, Tan S, Gao GF. Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies. Oncotarget. 2017 May 19;8(40):67129-67139. doi: 10.18632/oncotarget.18004. eCollection 2017 Sep 15. PMID: 28978021; PMCID: PMC5620161.
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Oncotarget. 2017 May 19;8(40):67129-67139. doi: 10.18632/oncotarget.18004. eCollection 2017 Sep 15.

Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies.

Oncotarget

Mengnan He, Yan Chai, Jianxun Qi, Catherine W H Zhang, Zhou Tong, Yi Shi, Jinghua Yan, Shuguang Tan, George F Gao

Affiliations

  1. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  2. University of Chinese Academy of Sciences, Beijing 100049, China.
  3. ImmuFuCell Biotechnology Co., Ltd., Beijing 100102, China.
  4. CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.

PMID: 28978021 PMCID: PMC5620161 DOI: 10.18632/oncotarget.18004

Abstract

Monoclonal antibody based immune checkpoint blockade therapies have achieved clinical successes in management of malignant tumors. As the first monoclonal antibody targeting immune checkpoint molecules entered into clinics, the molecular basis of ipilimumab-based anti-CTLA-4 blockade has not yet been fully understood. In the present study, we report the complex structure of ipilimumab and CTLA-4. The complex structure showed similar contributions from VH and VL of ipilimumab in binding to CTLA-4 front β-sheet strands. The blockade mechanism of ipilimumab is that the strands of CTLA-4 contributing to the binding to B7-1 or B7-2 were occupied by ipilimumab and thereafter prevents the binding of B7-1 or B7-2 to CTLA-4. Though ipilimumab binds to the same epitope with tremelimumab on CTLA-4 with similar binding affinity, the higher dissociation rate of ipilimumab may indicate the dynamic binding to CTLA-4, which may affect its pharmacokinetics. The molecular basis of ipilimumab-based anti-CTLA-4 blockade and comparative study of the binding characteristics of ipilimumab and tremelimumab would shed light for the discovery of small molecular inhibitors and structure-based monoclonal antibody optimization or new biologics.

Keywords: CTLA-4; complex structure; ipilimumab; tremelimumab

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest related to the publication of this work.

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