Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab

Abstract

// Fei Zhang 1, * , Xiaoqiang Qi 2, * , Xiaoxiao Wang 3, * , Diyang Wei 3 , Jiawei Wu 1 , Lingling Feng 1 , Haiyan Cai 1 , Yugang Wang 1 , Naiyan Zeng 1 , Ting Xu 3 , Aiwu Zhou 1 and Ying Zheng 1 1 Hongqiao 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 2 Faculty of Basic Medicine, Nanjing Medical University, Nanjing, China 3 The Therapeutic Antibody Research Center of SEU-Alphamab, Southeast University, Nanjing, China * These authors have contributed equally to this work Correspondence to: Aiwu Zhou, email: awz20@shsmu.edu.cn Ting Xu, email: tingxu@alphamab.com Ying Zheng, email: zhengyingsh@126.com Keywords: atezolizumab, PD-L1, crystal structure, immunotherapy, hot-spot residue Received: July 14, 2017      Accepted: August 29, 2017      Published: October 06, 2017 ABSTRACT 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 Å 2 , 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.