Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice.
BACKGROUND
Severe acute respiratory syndrome (SARS) remains a significant public health concern after the epidemic in 2003. Human monoclonal antibodies (MAbs) that neutralize SARS-associated coronavirus (SARS-CoV) could provide protection for exposed individuals.


METHODS
Transgenic mice with human immunoglobulin genes were immunized with the recombinant major surface (S) glycoprotein ectodomain of SARS-CoV. Epitopes of 2 neutralizing MAbs derived from these mice were mapped and evaluated in a murine model of SARS-CoV infection.


RESULTS
Both MAbs bound to S glycoprotein expressed on transfected cells but differed in their ability to block binding of S glycoprotein to Vero E6 cells. Immunoprecipitation analysis revealed 2 antibody-binding epitopes: one MAb (201) bound within the receptor-binding domain at aa 490-510, and the other MAb (68) bound externally to the domain at aa 130-150. Mice that received 40 mg/kg of either MAb prior to challenge with SARS-CoV were completely protected from virus replication in the lungs, and doses as low as 1.6 mg/kg offered significant protection.


CONCLUSIONS
Two neutralizing epitopes were defined for MAbs to SARS-CoV S glycoprotein. Antibodies to both epitopes protected mice against SARS-CoV challenge. Clinical trials are planned to test MAb 201, a fully human MAb specific for the epitope within the receptor-binding region.
Greenough
Thomas C
TC
Department of Pediatrics, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 02130, USA.
Babcock
Gregory J
GJ
Roberts
Anjeanette
A
Hernandez
Hector J
HJ
Thomas
William D
WD
Coccia
Jennifer A
JA
Graziano
Robert F
RF
Srinivasan
Mohan
M
Lowy
Israel
I
Finberg
Robert W
RW
Subbarao
Kanta
K
Vogel
Leatrice
L
Somasundaran
Mohan
M
Luzuriaga
Katherine
K
Sullivan
John L
JL
Ambrosino
Donna M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D005260:Female; D007116:Immunization, Passive; D008168:Lung / Q000821:virology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009500:Neutralization Tests; D011485:Protein Binding; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D045169:Severe Acute Respiratory Syndrome / Q000517:prevention & control*; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000939:Epitopes; D008562:Membrane Glycoproteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins