Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants.
In this report, the antiviral activity of 80R immunoglobulin G1 (IgG1), a human monoclonal antibody against severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) protein that acts as a viral entry inhibitor in vitro, was investigated in vivo in a mouse model. When 80R IgG1 was given prophylactically to mice at doses therapeutically achievable in humans, viral replication was reduced by more than 4 orders of magnitude to below assay limits. The essential core region of S protein required for 80R binding was identified as a conformationally sensitive fragment (residues 324 to 503) that overlaps the receptor ACE2-binding domain. Amino acids critical for 80R binding were identified. In addition, the effects of various 80R-binding domain amino acid substitutions which occur in SARS-like-CoV from civet cats, and which evolved during the 2002/2003 outbreak and in a 2003/2004 Guangdong index patient, were analyzed. The results demonstrated that the vast majority of SARS-CoVs are sensitive to 80R. We propose that by establishing the susceptibility and resistance profiles of newly emerging SARS-CoVs through early S1 genotyping of the core 180-amino-acid neutralizing epitope of 80R, an effective immunoprophylaxis strategy with 80R should be possible in an outbreak setting. Our study also cautions that for any prophylaxis strategy based on neutralizing antibody responses, whether by passive or active immunization, a genotyping monitor will be necessary for effective use.
Sui
Jianhua
J
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney St., JFB 824, Boston, MA 02115, USA. wayne_marasco@dfci.harvard.edu
Li
Wenhui
W
Roberts
Anjeanette
A
Matthews
Leslie J
LJ
Murakami
Akikazu
A
Vogel
Leatrice
L
Wong
Swee Kee
SK
Subbarao
Kanta
K
Farzan
Michael
M
Marasco
Wayne A
WA
D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology*; D000914:Antibodies, Viral / Q000008:administration & dosage* / Q000276:immunology*; D004195:Disease Models, Animal; D018604:Epitope Mapping; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000378:metabolism; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D045169:Severe Acute Respiratory Syndrome / Q000517:prevention & control* / Q000821:virology; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage* / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; C578557:spike glycoprotein, SARS-CoV; C578553:spike protein, mouse hepatitis virus