Abstract
SummaryThe emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC50 value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started emerging in humans in late 2019 and rapidly became a pandemic with millions of cases worldwide
COVID-19 patients with serum antibodies to the S1 subunit of the SARS-CoV-2 spike protein (Figure S1A; Table S1), we isolated two populations of single cells from peripheral blood mononuclear cells with fluorescence-activated cell sorting (FACS): CD19+CD27+CD38+ antibody-secreting cells (ASCs) reflecting the overall humoral immune response and SARS-CoV-2-S1labeled CD19+CD27+ memory B cells (S1-MBCs) for characterization of antigen-specific responses (Figures S1B and S1C)
Compared with monoclonal antibodies (mAbs) not reactive to SARS-CoV-2-S1, S1+ mAbs had fewer somatic hypermutations (SHMs) but equal lengths of their light- and heavy-chain complementarity-determining region 3 (CDR3) (Figures S1D–S1F)
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started emerging in humans in late 2019 and rapidly became a pandemic with millions of cases worldwide. SARS-CoV-2 infection causes coronavirus disease 2019 (COVID-19) with severe respiratory symptoms, pathological inflammation, and multi-organ dysfunction, including acute respiratory distress syndrome, cardiovascular events, coagulopathies, and neurological symptoms (Helms et al, 2020; Zhou et al, 2020; Zhu et al, 2020). Potent virus-neutralizing mAbs that were isolated from diverse variable immunoglobulin (Ig) genes typically carry low levels of somatic hypermutations (SHMs). Several of these neutralizing mAbs selected for in vitro efficacy showed prophylactic or therapeutic potential in animal
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