Non-overlapping epitopes on the gHgL-gp42 complex for the rational design of a triple-antibody cocktail against EBV infection

Junping Hong; Ling Zhong; Liqin Liu; Qian Wu; Wanlin Zhang; Kaiyun Chen; Dongmei Wei; Hui Sun; Xiang Zhou; Xinyu Zhang; Yin-Feng Kang; Yang Huang; Junyu Chen; Guosong Wang; Yan Zhou; Yanhong Chen; Qi-Sheng Feng; Hai Yu; Shaowei Li; Mu-Sheng Zeng; Yi-Xin Zeng; Miao Xu; Qingbing Zheng; Yixin Chen; Xiao Zhang; Ningshao Xia

doi:10.1016/j.xcrm.2023.101296

Non-overlapping epitopes on the gHgL-gp42 complex for the rational design of a triple-antibody cocktail against EBV infection

Cell Rep Med. 2023 Nov 21;4(11):101296. doi: 10.1016/j.xcrm.2023.101296.

Authors

Junping Hong¹, Ling Zhong², Liqin Liu³, Qian Wu³, Wanlin Zhang², Kaiyun Chen³, Dongmei Wei³, Hui Sun³, Xiang Zhou², Xinyu Zhang², Yin-Feng Kang², Yang Huang³, Junyu Chen³, Guosong Wang³, Yan Zhou², Yanhong Chen², Qi-Sheng Feng², Hai Yu³, Shaowei Li³, Mu-Sheng Zeng², Yi-Xin Zeng², Miao Xu⁴, Qingbing Zheng⁵, Yixin Chen⁶, Xiao Zhang⁷, Ningshao Xia⁸

Affiliations

¹ State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Research Unit of Frontier Technology of Structural Vaccinology of the Chinese Academy of Medical Sciences, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361005, China; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
² State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
³ State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Research Unit of Frontier Technology of Structural Vaccinology of the Chinese Academy of Medical Sciences, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361005, China.
⁴ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: xumiao@sysucc.org.cn.
⁵ State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Research Unit of Frontier Technology of Structural Vaccinology of the Chinese Academy of Medical Sciences, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361005, China. Electronic address: abing0811@xmu.edu.cn.
⁶ State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Research Unit of Frontier Technology of Structural Vaccinology of the Chinese Academy of Medical Sciences, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361005, China. Electronic address: yxchen2008@xmu.edu.cn.
⁷ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; College of Pharmacy, Chongqing Medical University, Chongqing 400016, China. Electronic address: 103193@cqmu.edu.cn.
⁸ State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Research Unit of Frontier Technology of Structural Vaccinology of the Chinese Academy of Medical Sciences, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361005, China. Electronic address: nsxia@xmu.edu.cn.

Abstract

Epstein-Barr virus (EBV) is closely associated with cancer, multiple sclerosis, and post-acute coronavirus disease 2019 (COVID-19) sequelae. There are currently no approved therapeutics or vaccines against EBV. It is noteworthy that combining multiple EBV glycoproteins can elicit potent neutralizing antibodies (nAbs) against viral infection, suggesting possible synergistic effects. Here, we characterize three nAbs (anti-gp42 5E3, anti-gHgL 6H2, and anti-gHgL 10E4) targeting different glycoproteins of the gHgL-gp42 complex. Two antibody cocktails synergistically neutralize infection in B cells (5E3+6H2+10E4) and epithelial cells (6H2+10E4) in vitro. Moreover, 5E3 alone and the 5E3+6H2+10E4 cocktail confer potent in vivo protection against lethal EBV challenge in humanized mice. The cryo-EM structure of a heptatomic gHgL-gp42 immune complex reveals non-overlapping epitopes of 5E3, 6H2, and 10E4 on the gHgL-gp42 complex. Structural and functional analyses highlight different neutralization mechanisms for each of the three nAbs. In summary, our results provide insight for the rational design of therapeutics or vaccines against EBV infection.

Keywords: Epstein-Barr virus; antibody cocktail; cryo-EM; gHgL-gp42 complex; neutralizing antibodies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / therapeutic use
Combined Antibody Therapeutics
Epitopes
Epstein-Barr Virus Infections*
Glycoproteins
Herpesvirus 4, Human
Membrane Glycoproteins
Mice
Vaccines*
Viral Envelope Proteins / chemistry
Viral Proteins

Substances

Viral Envelope Proteins
Membrane Glycoproteins
Viral Proteins
Combined Antibody Therapeutics
Epitopes
Glycoproteins
Antibodies, Neutralizing
Vaccines