Potent SARS-CoV-2 binding and neutralization through maturation of iconic SARS-CoV-1 antibodies

Abstract

Antibodies against coronavirus spike protein potently protect against infection and disease, but whether such protection can be extended to variant coronaviruses is unclear. This is exemplified by a set of iconic and well-characterized monoclonal antibodies developed after the 2003 SARS outbreak, including mAbs m396, CR3022, CR3014 and 80R, which potently neutralize SARS-CoV-1, but not SARS-CoV-2. Here, we explore antibody engineering strategies to change and broaden their specificity, enabling nanomolar binding and potent neutralization of SARS-CoV-2. Intriguingly, while many of the matured clones maintained specificity of the parental antibody, new specificities were also observed, which was further confirmed by X-ray crystallography and cryo-electron microscopy, indicating that a limited set of VH antibody domains can give rise to variants targeting diverse epitopes, when paired with a diverse VL repertoire. Our findings open up over 15 years of antibody development efforts against SARS-CoV-1 to the SARS-CoV-2 field and outline general principles for the maturation of antibody specificity against emerging viruses.

SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

“…Thus, even with the 17.3-fold decrease in neutralisation titre, boosting with mRNA vaccines is predicted to provide signi cant protection from infection with Omicron (Table 1 The Omicron variant contains several mutations at RBD sites, previously thought to be highly conserved, that are the target of antibody therapeutics. For example, S371L, S373P, and S375F form part of the class 4 epitope, affecting previously described class 4 antibodies such as Ab-3467 that broadly neutralise sarbecoviruses 13,14 . Additional mutations unique to Omicron at sites 417, 440, 446, and 493 are likely to contribute to the lack of the neutralisation of other therapeutic antibodies.…”

SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

“…Casirivimab, Imdevimab, Bamlanivimab, Cilgavimab, and Ab-3467 did not neutralize at the highest concentrations tested (Table 2 The Omicron variant contains several mutations at RBD sites previously thought to be highly conserved that are the target of antibody therapeutics. For example, S371L, S373P, and S375F form part of the class 4 epitope, affecting previously described class 4 antibodies such as Ab-3467 that broadly neutralize sarbecoviruses 7,8 . Additional mutations unique to Omicron at sites 417, 440, 446, and 493 are likely to contribute to the lack of the neutralisation of other therapeutic antibodies.…”

Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift

“… 25 , 35 However, the magnitude of this effect depends largely on the epitope recognized by the antibody and the initial affinity along with the format of the antibody and its valence. 25 Several recent studies have described affinity maturation of VHH or conventional antibodies to enhance their binding to SARS-CoV-2 antigens, by CDR-swapping approaches, 36 saturation mutagenesis in CDRs 37 , 38 or light-chain shuffling. 38 …”