TY - JOUR T1 - Engineering SARS-CoV-2 neutralizing antibodies for increased potency and reduced viral escape JF - bioRxiv DO - 10.1101/2022.01.06.475303 SP - 2022.01.06.475303 AU - Fangzhu Zhao AU - Celina Keating AU - Gabriel Ozorowski AU - Namir Shaabani AU - Irene M. Francino-Urdaniz AU - Shawn Barman AU - Oliver Limbo AU - Alison Burns AU - Panpan Zhou AU - Michael J. Ricciardi AU - Jordan Woehl AU - Quoc Tran AU - Hannah L. Turner AU - Linghang Peng AU - Deli Huang AU - David Nemazee AU - Raiees Andrabi AU - Devin Sok AU - John R. Teijaro AU - Timothy A. Whitehead AU - Andrew B. Ward AU - Dennis R. Burton AU - Joseph G. Jardine Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/07/2022.01.06.475303.abstract N2 - The rapid spread of SARS-CoV-2 variants poses a constant threat of escape from monoclonal antibody and vaccine countermeasures. Mutations in the ACE2 receptor binding site on the surface S protein have been shown to disrupt antibody binding and prevent viral neutralization. Here, we use a directed evolution-based approach to engineer three neutralizing antibodies for enhanced binding to S protein. The engineered antibodies showed increased in vitro functional activity in terms of neutralization potency and/or breadth of neutralization against viral variants. Deep mutational scanning revealed that higher binding affinity reduced the total number of viral escape mutations. Studies in the Syrian hamster model showed two examples where the affinity matured antibody provided superior protection compared to the parental antibody. These data suggest that monoclonal antibodies for anti-viral indications could benefit from in vitro affinity maturation to reduce viral escape pathways and appropriate affinity maturation in vaccine immunization could help resist viral variation.Competing Interest StatementJ.G.J., D.R.B., and F.Z. are listed as inventors on pending patent applications describing the engineered SARS-CoV-2 neutralizing antibodies. ER -