Abstract
The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants. Here we show that the bivalency of an affinity maturated fully human single-domain antibody (n3113.1-Fc) exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus, and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2 (ACE2) humanized mice. The crystal structure of n3113 in complex with the receptor-binding domain (RBD) of SARS-CoV-2, combined with the cryo-EM structures of n3113 and spike ecto-domain, reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2. The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion, expanding our recognition of neutralization by antibodies against SARS-CoV-2. Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) for n3113.1-Fc with Y58L mutation, demonstrating the potential of n3113.1-Fc (Y58L) as a promising candidate for clinical development to treat COVID-19.
Highlights
SARS-CoV-2 has been considered as the third coronavirus causing a major outbreak following SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), all of which belong to the betacoronavirus genus.[6,7]
Of 940 Å2 buried surface area (BSA), CDR3 accounts for 375 Å2. 7 (W99-T104 and D106) of the 12 residues in CDR3 participate in the interaction with receptor-binding domain (RBD), forming 7
To improve the binding affinity of n3113 with SARSCoV-2 RBD, we introduced diversity into n3113 through errorprone PCR and generated a phage display library with an estimated diversity of 6 × 109 (Supplementary Fig. 1a)
Summary
The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented damage to global health and the economy.[1,2,3] The. Yang et al. In addition, with the emerging prevalence of SARS-CoV-2 mutant Structural basis of n3113 binding modes at RBD and S trimer strains constantly challenging the efficacy of current treatments, it To better understand the molecular feature of the interaction is imperative to investigate the neutralization mechanism for pattern between RBD and n3113 and to provide insight into the different types of antibodies, providing the basis for the rational neutralization mechanism of n3113, we determined the crystal design of antibody combinations with synergistic effect and structure of n3113 in complex with RBD at a resolution of 2.27 Å avoiding immune escape. Human single-domain antibody with high neutralizing potency against SARS-CoV-2 and its prevalent variants. Of 940 Å2 buried surface area (BSA), CDR3 accounts for 375 Å2. 7 (W99-T104 and D106) of the 12 residues in CDR3 participate in the interaction with RBD, forming 7
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