A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2

TLDR

Developing therapeutics against SARS‑CoV‑2 requires knowledge of epitope distribution across the Spike protein, not just the RBD. The authors isolated monoclonal antibodies from ten convalescent patients and used cryo‑electron microscopy to map the 4A8 epitope to the N‑terminal domain of the Spike protein at 3.1‑Å resolution. Three antibodies neutralized authentic SARS‑CoV‑2, and the potent 4A8 antibody binds the N‑terminal domain rather than the RBD, highlighting the NTD as a promising therapeutic target.

Abstract

Developing therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from 10 convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. One mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2 but does not bind the RBD. We defined the epitope of 4A8 as the N-terminal domain (NTD) of the S protein by determining with cryo-eletron microscopy its structure in complex with the S protein to an overall resolution of 3.1 angstroms and local resolution of 3.3 angstroms for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19.