Journal
MABS
Volume 13, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2021.1922134
Keywords
Monoclonal antibodies; antibody maturation; antibody engineering; phage display; SARS-CoV-2; structural studies
Categories
Funding
- NSW Government
- Medical Research Future Fund [2001739]
- National Health and Medical Research Council [1016953, 1113904, 1108800, 585490, 1157744, 190774, 1176351, 1159347, 1081858]
- DECRA Fellowship from the Australian Research Council [DE190100985]
- [160104915]
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This study investigates how to alter and broaden the specificity of existing antibodies to effectively neutralize SARS-CoV-2. The research shows that while some clones maintain the specificity of the parental antibody, new specificities also emerge, leading to the development of variants targeting diverse epitopes when paired with a diverse VL repertoire.
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.
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