tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2020 Nov 2;202010197.
doi: 10.1073/pnas.2010197117. Online ahead of print.
Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection
Wei Li[SUP] 1 [/SUP], Chuan Chen[SUP] 2 [/SUP], Aleksandra Drelich[SUP] 3 [/SUP], David R Martinez[SUP] 4 [/SUP], Lisa E Gralinski[SUP] 4 [/SUP], Zehua Sun[SUP] 2 [/SUP], Alexandra Sch?fer[SUP] 4 [/SUP], Swarali S Kulkarni[SUP] 5 [/SUP], Xianglei Liu[SUP] 2 [/SUP], Sarah R Leist[SUP] 4 [/SUP], Doncho V Zhelev[SUP] 2 [/SUP], Liyong Zhang[SUP] 2 [/SUP], Ye-Jin Kim[SUP] 2 [/SUP], Eric C Peterson[SUP] 6 [/SUP], Alex Conard[SUP] 6 [/SUP], John W Mellors[SUP] 2 6 [/SUP], Chien-Te K Tseng[SUP] 3 [/SUP], Darryl Falzarano[SUP] 5 [/SUP], Ralph S Baric[SUP] 4 [/SUP], Dimiter S Dimitrov[SUP] 1 6 [/SUP]
Affiliations
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.
Keywords: SARS-CoV-2; animal models; coronaviruses; therapeutic antibodies.
. 2020 Nov 2;202010197.
doi: 10.1073/pnas.2010197117. Online ahead of print.
Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection
Wei Li[SUP] 1 [/SUP], Chuan Chen[SUP] 2 [/SUP], Aleksandra Drelich[SUP] 3 [/SUP], David R Martinez[SUP] 4 [/SUP], Lisa E Gralinski[SUP] 4 [/SUP], Zehua Sun[SUP] 2 [/SUP], Alexandra Sch?fer[SUP] 4 [/SUP], Swarali S Kulkarni[SUP] 5 [/SUP], Xianglei Liu[SUP] 2 [/SUP], Sarah R Leist[SUP] 4 [/SUP], Doncho V Zhelev[SUP] 2 [/SUP], Liyong Zhang[SUP] 2 [/SUP], Ye-Jin Kim[SUP] 2 [/SUP], Eric C Peterson[SUP] 6 [/SUP], Alex Conard[SUP] 6 [/SUP], John W Mellors[SUP] 2 6 [/SUP], Chien-Te K Tseng[SUP] 3 [/SUP], Darryl Falzarano[SUP] 5 [/SUP], Ralph S Baric[SUP] 4 [/SUP], Dimiter S Dimitrov[SUP] 1 6 [/SUP]
Affiliations
- PMID: 33139569
- DOI: 10.1073/pnas.2010197117
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.
Keywords: SARS-CoV-2; animal models; coronaviruses; therapeutic antibodies.