De novo design of high-affinity antibody variable regions (scFv) against the SARS-CoV-2 spike protein

Abstract

The emergence of SARS-CoV-2 is responsible for the pandemic of respiratory disease known as COVID-19, which emerged in the city of Wuhan, Hubei province, China in late 2019. Both vaccines and targeted therapeutics for treatment of this disease are currently lacking. Viral entry requires binding of the viral spike receptor binding domain (RBD) with the human angiotensin converting enzyme (hACE2). In an earlier paper1, we report on the specific residue interactions underpinning this event. Here we report on the de novo computational design of high affinity antibody variable regions through the recombination of VDJ genes targeting the most solvent-exposed hACE2-binding residues of the SARS-CoV-2 spike protein using the software tool OptMAVEn-2.02. Subsequently, we carry out computational affinity maturation of the designed prototype variable regions through point mutations for improved binding with the target epitope. Immunogenicity was restricted by preferring designs that match sequences from a 9-mer library of "human antibodies" based on H-score (human string content, HSC)3. We generated 106 different designs and report in detail on the top five that trade-off the greatest affinity for the spike RBD epitope (quantified using the Rosetta binding energies) with low H-scores. By grafting the designed Heavy (VH) and Light (VL) chain variable regions onto a human framework (Fc), high-affinity and potentially neutralizing full-length monoclonal antibodies (mAb) can be constructed. Having a potent antibody that can recognize the viral spike protein with high affinity would be enabling for both the design of sensitive SARS-CoV-2 detection devices and for their deployment as therapeutic antibodies.