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

// Mengnan He 1, 2, * , Yan Chai 1, * , Jianxun Qi 1 , Catherine W.H. Zhang 3 , Zhou Tong 4 , Yi Shi 1 , Jinghua Yan 4 , Shuguang Tan 1 and George F. Gao 1, 2 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 * These authors have contributed equally to this work Correspondence to: George F. Gao, email: gaof@im.ac.cn Shuguang Tan, email: tansg@im.ac.cn Keywords: ipilimumab, CTLA-4, complex structure, tremelimumab Received: April 04, 2017 Accepted: April 21, 2017 Published: May 19, 2017 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.