Identification of potent human neutralizing antibodies against SARS-CoV-2 implications for development of therapeutics and prophylactics

Shaojuan Zhao,Huajun Zhang,Yancheng Zhan,Xiaoqing Zhang,Zhe Zhang,Haiwei Zhang,Rui Gong,Zhengli Shi,Cheng Peng,Rendi Jiang,Meiqin Liu,Xinglou Yang,Xiaoxiao Gao,Lan Liu,Wei Tang,Li Chen,Ying Chen

doi:10.1038/s41467-021-25153-x

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that is spreading rapidly, which seriously impacts global public health and economy. Thus, developing effective drugs remains urgent. We identify two potent antibodies, nCoVmab1 and nCoVmab2, targeting the SARS-CoV-2 spike protein receptor-binding domain (RBD) with high affinities from a naïve human phage-displayed Fab library. nCoVmab1 and nCoVmab2 neutralize authentic SARS-CoV-2 with picomolar and nanomolar IC50 values, respectively. No detectable defects of nCoVmab1 and nCoVmab2 are found during the preliminary druggability evaluation. nCoVmab1 could reduce viral titer and lung injury when administered prophylactically and therapeutically in human angiotensin-converting enzyme II (hACE2)-transgenic mice. Therefore, phage display platform could be efficiently used for rapid development of neutralizing monoclonal antibodies (nmabs) with clinical potential against emerging infectious diseases. In addition, we determinate epitopes in RBD of these antibodies to elucidate the neutralizing mechanism. We also convert nCoVmab1 and nCoVmab2 to their germline formats for further analysis, which reveals the contribution of somatic hypermutation (SHM) during nCoVmab1 and nCoVmab2 maturation. Our findings not only provide two highly potent nmabs against SARS-CoV-2 as prophylactic and therapeutic candidates, but also give some clues for development of anti-SARS-CoV-2 agents (e.g., drugs and vaccines) targeting the RBD.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that is spreading rapidly, which seriously impacts global public health and economy
Numerous neutralizing monoclonal antibodies targeting the receptor-binding domain (RBD) have been developed for severe acute respiratory syndrome coronavirus (SARS-CoV)[7] and Middle East respiratory syndrome coronavirus (MERS-CoV)[8]
An in-house constructed large naïve human phage-displayed Fab library was used for panning against biotinylated RBD-Fc with magnetic beads

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that is spreading rapidly, which seriously impacts global public health and economy. We identify two potent antibodies, nCoVmab[1] and nCoVmab[2], targeting the SARS-CoV-2 spike protein receptor-binding domain (RBD) with high affinities from a naïve human phage-displayed Fab library. Numerous neutralizing monoclonal antibodies (nmabs) targeting the RBD have been developed for severe acute respiratory syndrome coronavirus (SARS-CoV)[7] and Middle East respiratory syndrome coronavirus (MERS-CoV)[8]. These antibodies are potential therapeutics for clinical use[9]. We report the identification of two neutralizing antibodies, nCoVmab[1] and nCoVmab[2], against SARS-CoV-2, from a large naïve human phage-displayed Fab library. We investigate the binding abilities of the germline formats of nCoVmab[1] and nCoVmab[2] to the RBD, which preliminarily discloses the complexity and significance of the antibody maturation pathway for eliciting highly potent neutralizing antibodies by RBD

Methods

Results

Conclusion