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bioRxiv · 10.1101/2021.01.11.426218

Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class

Rapp, M.·Guo, Y.·Reddem, E. R.·Liu, L.·Wang, P.·Yu, J.·Cerutti, G.·Bimela, J.·Bahna, F.·Mannepalli, S.·Zhang, B.·Kwong, P. D.·Ho, D. D.·Shapiro, L.·Sheng, Z.
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Abstract

Antibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent SARS-CoV-2-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determined structures of the SARS-CoV-2 spike in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three utilized VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy chain N53I enhancing binding and light chain tyrosines recognizing F486RBD. Despite these similarities, class members bound both RBD-up and -down conformations of the spike, with a subset of antibodies utilizing elongated CDRH3s to recognize glycan N343 on a neighboring RBD - a quaternary interaction accommodated by an increase in RBD separation of up to 12 [A]. The VH1-2-antibody class thus utilizes modular recognition encoded by modular genetic elements to effect potent neutralization, with VH-gene component specifying recognition of RBD and CDRH3 component specifying quaternary interactions. HighlightsO_LIDetermine structures of VH1-2-derived antibodies 2-43, 2-15, and H4 in complex with SARS-CoV-2 spike C_LIO_LIDefine a multi-donor VH1-2-antibody class with modular components for RBD and quaternary recognition C_LIO_LIReveal structural basis of RBD-up and RBD-down recognition within the class C_LIO_LIShow somatic hypermutations and avidity to be critical for potency C_LIO_LIDelineate changes in spike conformation induced by CDRH3-mediated quaternary recognition C_LI

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Rapp, M., Guo, Y., Reddem, E. R., Liu, L., Wang, P., Yu, J., Cerutti, G., Bimela, J., Bahna, F., Mannepalli, S., Zhang, B., Kwong, P. D., Ho, D. D., Shapiro, L., Sheng, Z.. 2021-01-11. Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class. https://doi.org/10.1101/2021.01.11.426218

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