Abstract
Effective therapies are urgently needed for the SARS-CoV-2/COVID-19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from large phage-displayed Fab, scFv, and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. A high-affinity Fab was selected from one of the libraries and converted to a full-size antibody, IgG1 ab1, which competed with human ACE2 for binding to RBD. It potently neutralized replication-competent SARS-CoV-2 but not SARS-CoV, as measured by two different tissue culture assays, as well as a replication-competent mouse ACE2-adapted SARS-CoV-2 in BALB/c mice and native virus in hACE2-expressing transgenic mice showing activity at the lowest tested dose of 2 mg/kg. IgG1 ab1 also exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection. The mechanism of neutralization is by competition with ACE2 but could involve antibody-dependent cellular cytotoxicity (ADCC) as IgG1 ab1 had ADCC activity in vitro. The ab1 sequence has a relatively low number of somatic mutations, indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection or by RBD-based vaccines. IgG1 ab1 did not aggregate, did not exhibit other developability liabilities, and did not bind to any of the 5,300 human membrane-associated proteins tested. These results suggest that IgG1 ab1 has potential for therapy and prophylaxis of SARS-CoV-2 infections. The rapid identification (within 6 d of availability of antigen for panning) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes.
Highlights
Effective therapies are urgently needed for the SARS-CoV-2/ COVID-19 pandemic
By using phage display we have previously identified a number of potent fully human monoclonal antibodies (mAbs) (m396, m336, and m102.4) against emerging viruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) [3], Middle East respiratory syndrome coronavirus (MERS-CoV) [4], and henipaviruses [5, 6], respectively, which are highly effective in animal models of infection [7,8,9,10]; one of them was administered on a compassionate basis to humans exposed to henipaviruses and successfully evaluated in a clinical trial [11]
The human angiotensin-converting enzyme 2 (hACE2)-competing antibodies ab2, 3, 9, and m398 competed with ab1, while the hACE2-noncompeting antibodies did not compete with ab1 for binding to receptor binding domain (RBD) (SI Appendix, Fig. S3C)
Summary
Effective therapies are urgently needed for the SARS-CoV-2/ COVID-19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from large phage-displayed Fab, scFv, and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. We rapidly (within a week) identified a fully human monoclonal germline-like antibody (ab1) from phage-displayed libraries that potently inhibited mouse ACE2-adapted SARS-CoV-2 replication in wildtype BALB/c mice and native virus in transgenic mice expressing human ACE2 as well as in hamsters when administered before virus challenge. It was effective when administered after virus infection of hamsters, at lower efficacy than when used prophylactically. Ab1 has potential for prophylaxis and therapy of COVID-19 alone or in combination with other agents
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