Rapid discovery of diverse neutralizing SARS-CoV-2 antibodies from large-scale synthetic phage libraries

MABS 2022 | VOL. 14 | NO. 1 | 30 DEC 2021

Tom Z. Yuan, Pankaj Garg, Linya Wang, Jordan R. Willis, Eric Kwan, Ana G Lujan Hernandez, Emily Tuscano, Emily N. Sever, Erica Keane, Cinque Soto, Eric M. Mucker, Mallorie E. Fouch, Edgar Davidson, Benjamin J. Doranz, Shweta Kailasan, M. Javad Aman, Haoyang Li, Jay W. Hooper, Erica Ollmann Saphire, James E. Crowe, Qiang Liu, Fumiko Axelrod & Aaron K. Sato

Abstract

Coronavirus disease 2019 (COVID-19) is an evolving global public health crisis in need of therapeutic options. Passive immunization of monoclonal antibodies (mAbs) represents a promising therapeutic strategy capable of conferring immediate protection from SARS-CoV-2 infection. Herein, we describe the discovery and characterization of neutralizing SARS-CoV-2 IgG and VHH antibodies from four large-scale phage libraries. Each library was constructed synthetically with shuffled complementarity-determining region loops from natural llama and human antibody repertoires. While most candidates targeted the receptor-binding domain of the S1 subunit of SARS-CoV-2 spike protein, we also identified a neutralizing IgG candidate that binds a unique epitope on the N-terminal domain. A select number of antibodies retained binding to SARS-CoV-2 variants Alpha, Beta, Gamma, Kappa and Delta. Overall, our data show that synthetic phage libraries can rapidly yield SARS-CoV-2 S1 antibodies with therapeutically desirable features, including high affinity, unique binding sites, and potent neutralizing activity in vitro, and a capacity to limit disease in vivo.

Introduction

Severe acute respiratory syndrome coronavirus two (SARS-CoV -2) causes COVID-19, a respiratory infection that can ultimately lead to severe pneumonia, acute respiratory failure, and death. Following the Wuhan outbreak in December 2019, SARS-CoV -2 quickly achieved global, pandemic spread, culminating in 246,889,661 global cases and 5,003,021 global deaths as of November 1, 2021. Safe and effective therapies are therefore needed to combat the transmissibility, pathogenicity, and disease severity of SARS-CoV-2 as new variants of concern emerge. Passive antibody therapy using either convalescent plasma from recovered COVID-19 survivors or monoclonal antibodies (mAbs) has proven safe and effective against other betacoronaviruses such as Middle East respiratory syndrome-related coronavirus (MERS-CoV) and SARS-CoV. Although convalescent plasma is readily available and approved for use in critically ill COVID-19 patients, it must be screened for blood-borne pathogens, requires high titers for therapeutic efficacy, and can pose rare but nevertheless notable risks, including transfusion-related acute lung injury, transfusion-associated dyspnea, circulatory overload, and allergic reactions. These risks can be subjugated through the use of recombinant neutralizing mAbs, the therapeutic agent of convalescent plasma.