Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab
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Fei Zhang1,*, Xiaoqiang Qi2,*, Xiaoxiao Wang3,*, Diyang Wei3, Jiawei Wu1, Lingling Feng1, Haiyan Cai1, Yugang Wang1, Naiyan Zeng1, Ting Xu3, Aiwu Zhou1 and Ying Zheng1
1Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2Faculty of Basic Medicine, Nanjing Medical University, Nanjing, China
3The Therapeutic Antibody Research Center of SEU-Alphamab, Southeast University, Nanjing, China
*These authors have contributed equally to this work
Aiwu Zhou, email: firstname.lastname@example.org
Ting Xu, email: email@example.com
Ying Zheng, email: firstname.lastname@example.org
Keywords: atezolizumab, PD-L1, crystal structure, immunotherapy, hot-spot residue
Received: July 14, 2017 Accepted: August 29, 2017 Published: October 06, 2017
Monoclonal antibodies targeting PD-1/PD-L1 signaling pathway have achieved unprecedented success in cancer treatment over the last few years. Atezolizumab is the first PD-L1 monoclonal antibody approved by US FDA for cancer therapy; however the molecular basis of atezolizumab in blocking PD-1/PD-L1 interaction is not fully understood. Here we have solved the crystal structure of PD-L1/atezolizumab complex at 2.9 angstrom resolution. The structure shows that atezolizumab binds the front beta-sheet of PD-L1 through three CDR loops from the heavy chain and one CDR loop from the light chain. The binding involves extensive hydrogen-bonding and hydrophobic interactions. Notably there are multiple aromatic residues from the CDR loops forming Pi-Pi stacking or cation-Pi interactions within the center of the binding interface and the buried surface area is more than 2000 Å2, which is the largest amongst all the known PD-L1/antibody structures. Mutagenesis study revealed that two hot-spot residues (E58, R113) of PD-L1 contribute significantly to the binding of atezolizumab. The structure also shows that atezolizumab binds PD-L1 with a distinct heavy and light chain orientation and it blocks PD-1/PD-L1 interaction through competing with PD-1 for the same PD-L1 surface area. Taken together, the complex structure of PD-L1/atezolizumab solved here revealed the molecular mechanism of atezolizumab in immunotherapy and provides basis for future monoclonal antibody optimization and rational design of small chemical compounds targeting PD-L1 surface.
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