AI Designed Mutation Resistant Broad Neutralization Antibodies Against Multiple SARS-CoV-2 Strains based on A Digital Twin of COVID-19 - Case study

Introduction

• The emerging variants including Delta and Omicron may not retain activity with current available mAb products that were developed during the initial outbreak with the B.l strain.
• In this study, we have applied AI technologies in the computational design of broad neutralization antibodies against over 1300 different historical SARS-CoV-2 strains with very small computational cost.
• These Al-designed antibodies also exhibited a very high cross-binding hit rate against different Spike protein RBD region mutants in ELISA assay.
• The Al-designed antibodies were tested in vitro and demonstrated high potency against multiple strains in real virus neutralization assays.

Methods and Data

• In the study of SARS-Cov-2, 1300 different historical SARS-CoV-2 strains data was collected from based on the GISAID"112"31 database as of August 26,2021
• The first round of Al-based antibody design was performed on selected antibody templates14"51 in order to increase binding affinities with respect to over 1300 different historical SARS-CoV-2 strains including wildtypc(B.l) strain and Delta strain. Our large molecule virtual screening platform was able to search 1010 somatic mutation space and 50 cross-binding antibody sequences were designed across different strains.
• The second round antibody design was performed during the prevalence of Omicron strain, in which same computational approach was employed with Omicron strain included. 20 cross-binding antibody sequences were designed.

Experiments Results
The first batch of 50 antibodies and second batch of 20 antibodies are well-expressed with high hit rate on positive affinity against B.l, Delta and Omicron. The two batches yield 14% and 40% triple cross binding hit rates respectively. Affinity maturation against Omicron on three different template antibodies were optimized up to 269.65 fold increase.

Dose dependent ELISA binding test was also performed on antibodies and controls against Sars-CoV-2 Wild type (B.l), Delta and Omicron RBD proteins to determine the IC50 value.

Real Virus Neutralization: the antivirus effect of designed antibodies was evaluated by cell-based assay measuring the cytopathic effect (CPE) of the virus infecting Vero E6 host cells against Delta and Omicron strains. 10 antibodies show neutralization effect on Delta Strain(with IC50 <10ug/ml). 1 antibody shows effect on Omicron Strain