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

Rapp, Micah; Guo, Yicheng; Reddem, Eswar R.; Yu, Jian; Liu, Lihong; Wang, Pengfei; Cerutti, Gabriele; Katsamba, Phinikoula; Bimela, Jude S.; Bahna, Fabiana A.; Mannepalli, Seetha M.; Zhang, Baoshan; Kwong, Peter D.; Huang, Yaoxing; Ho, David D.; Shapiro, Lawrence; Sheng, Zizhang

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 utilize 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 bind 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 Å. 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.