Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms

Abstract

Efficient therapeutic options are needed to control the spread of SARS-CoV-2 that has caused more than 922,000 fatalities as of September 13th, 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block ACE2 attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Cocktails including S2M11, S2E12 or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.

Antibody response and therapy in COVID-19 patients: what can be learned for vaccine development?

“…These neutralizing mAbs were derived from four different sources. The largest panel of neutralizing antibodies is from the peripheral blood of COVID-19 patients via sorting antigen-specific B lymphocytes and cloning paired heavy and light chains of anti-SARS-CoV-2-specific immunoglobulin (Brouwer et al, 2020; Chi et al, 2020; Hansen et al, 2020; Ju et al, 2020; Robbiani et al, 2020;Rogers et al, 2020;Seydoux et al, 2020;Shi et al, 2020;Tortorici et al, 2020;Wan et al, 2020a;Wu et al, 2020c;Zost et al, 2020) (Table 2). The second category of neutralizing mAbs were identified from previously isolated anti-SARS-CoV mAbs by testing their cross-reactivities to SARS-CoV-2 antigens (Ejemel et al, 2020;Huo et al, 2020;Pinto et al, 2020;Tai et al, 2020;Tian et al, 2020;Wec et al, 2020;Yuan et al, 2020b).…”

An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

“…Strategies to prevent SARS-CoV-2 entry into the host cell aim to block the ACE2-RBD interaction. Although high-affinity monoclonal antibodies are leading the way as potential therapeutics (20,(23)(24)(25)(26)(27)(28)(29)(30), they are expensive to produce by mammalian cell expression and need to be intravenously administered by healthcare professionals (31). Large doses are needed for prophylactic use, as only a small fraction of systemic antibodies cross the epithelial cell layers lining the airways (32).…”

“…In the case of Nb6 and mNb6, structure-guided design of a multimeric construct that simultaneously engages all three RBDs yielded profound gains in potency. Furthermore, because RBDs must be in the up-state to engage with ACE2, conformational control of RBD accessibility serves as an added neutralization mechanism (30). Indeed, when mNb6-tri engages with Spike, it prevents ACE2 binding by both directly occluding the binding site and by locking the RBDs into an inactive conformation.…”

Evolution of Antibody Immunity to SARS-CoV-2

“…To determine whether the antibodies expressed by memory B cells at the late time point also showed altered breadth, we compared them to earlier clonal relatives in binding assays using control and mutant RBDs: The mutations E484K and Q493R 15 were selected for resistance to class 2 antibodies such as C144 and C121 that bind directly to the ACE2 interaction ridge in the RBD 1,[16][17][18] while R346S, N439K, and N440K were selected for resistance to class 3 antibodies such as C135 that do not directly interfere with ACE2 binding 1,[15][16][17][18] (Fig.3c). In addition, V367F, A475V, S477N, and V483A represent circulating variants that confer complete or partial resistance to class 1 and 2 antibodies 15,16,19 (Fig.…”