A pair of noncompeting neutralizing human monoclonal antibodies protecting from disease in a SARS-CoV-2 infection model

被引：30

作者：

Peter, Antonia Sophia ^{[1
]}

Roth, Edith ^{[2
]}

Schulz, Sebastian R. ^{[2
]}

Fraedrich, Kirsten ^{[1
]}

Steinmetz, Tobit ^{[2
]}

Damm, Dominik ^{[1
]}

Hauke, Manuela ^{[2
]}

Richel, Elie ^{[1
]}

Mueller-Schmucker, Sandra ^{[1
]}

Habenicht, Katharina ^{[3
]}

Eberlein, Valentina ^{[4
]}

Issmail, Leila ^{[4
]}

Uhlig, Nadja ^{[4
]}

Dolles, Simon ^{[5
]}

Gruner, Eva ^{[1
]}

Peterhoff, David ^{[6
,7
]}

Ciesek, Sandra ^{[8
,9
,10
]}

Hoffmann, Markus ^{[11
]}

Pohlmann, Stefan ^{[11
]}

McKay, Paul F. ^{[12
]}

Shattock, Robin J. ^{[12
]}

Wolfel, Roman ^{[13
,14
]}

Socher, Eileen ^{[15
,16
]}

Wagner, Ralf ^{[6
]}

Eichler, Jutta ^{[5
]}

Sticht, Heinrich ^{[15
]}

Schuh, Wolfgang ^{[2
]}

Neipel, Frank ^{[1
]}

Ensser, Armin ^{[1
]}

Mielenz, Dirk ^{[2
]}

Tenbusch, Matthias ^{[1
]}

Winkler, Thomas H.

Grunwald, Thomas

Uberla, Klaus ^{[1
]}

Jack, Hans-Martin ^{[2
]}

机构：

[1] Friedrich Alexander Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Clin & Mol Virol, Erlangen, Germany

[2] Friedrich Alexander Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Internal Med 3, Div Mol Immunol, Erlangen, Germany

[3] Friedrich Alexander Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Dept Biol, Div Genet, Erlangen, Germany

[4] Fraunhofer Inst Cell Therapy & Immunol IZI, Dept Immunol, Leipzig, Germany

[5] Friedrich Alexander Univ Erlangen Nurnberg, Dept Chem & Pharm, Erlangen, Germany

[6] Univ Regensburg, Mol Microbiol Virol, Inst Med Microbiol & Hyg, Regensburg, Germany

[7] Univ Hosp Regensburg, Inst Clin Microbiol & Hyg, Regensburg, Germany

[8] Goethe Univ Frankfurt, Univ Hosp Frankfurt, Inst Med Virol, Frankfurt, Germany

[9] German Ctr Infect Res, External Partner Site, Frankfurt, Germany

[10] Fraunhofer Inst Mol Biol & Appl Ecol IME, Branch Translat Med & Pharmacol, Frankfurt, Germany

[11] German Primate Ctr, Infect Biol Unit, Gottingen, Germany

[12] Imperial Coll London, Dept Infect Dis, London, England

[13] Bundeswehr Inst Microbiol, Munich, Germany

[14] German Ctr Infect Res, Partner Site Munich, Munich, Germany

[15] Friedrich Alexander Univ Erlangen Nurnberg, Inst BiochemistryEmilF Ctr, Div Bioinformat, Erlangen, Germany

[16] Friedrich Alexander Univ Erlangen Nurnberg, Inst Anat Funct & Clin Anat, Erlangen, Germany

来源：

EUROPEAN JOURNAL OF IMMUNOLOGY | 2022年 / 52卷 / 05期

关键词：

COVID-19; neutralizing antibodies; spike protein; SARS-CoV-2; variants of concern; CELL; EVOLUTION; BROAD; SPIKE;

D O I：

10.1002/eji.202149374

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.

引用

页码：770 / 783

页数：14

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