Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice
Department of Pediatrics; Massachusetts Biologic Laboratories; Program in Molecular Medicine
Medical Subject Headings
Animals; Antibodies, Monoclonal; Antibodies, Viral; Cells, Cultured; Disease Models, Animal; Epitope Mapping; Epitopes; Female; *Immunization, Passive; Lung; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Transgenic; Neutralization Tests; Protein Binding; SARS Virus; Severe Acute Respiratory Syndrome; Viral Envelope Proteins
Immunology and Infectious Disease | Pediatrics
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.
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Citation: J Infect Dis. 2005 Feb 15;191(4):507-14. Epub 2005 Jan 14. Link to article on publisher's site
Greenough, Thomas C.; Babcock, Gregory J.; Roberts, Anjeanette; Hernandez, Hector J.; Thomas, William D.; Coccia, Jennifer A.; Graziano, Robert F.; Srinivasan, Mohan; Lowy, Israel; Finberg, Robert W.; Subbarao, Kanta; Vogel, Leatrice; Somasundaran, Mohan; Luzuriaga, Katherine; Sullivan, John L.; and Ambrosino, Donna M., "Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice" (2005). Immunology/Infectious Disease. Paper 47.