Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases.
Using a comprehensive set of discovery and optimization tools, antibodies were produced with the ability to neutralize SARS coronavirus (SARS-CoV) infection in Vero E6 cells and in animal models. These anti-SARS antibodies were discovered using a novel DNA display method, which can identify new antibodies within days. Once neutralizing antibodies were identified, a comprehensive and effective means of converting the mouse sequences to human frameworks was accomplished using HuFR (human framework reassembly) technology. The best variant (61G4) from this screen showed a 3.5-4-fold improvement in neutralization of SARS-CoV infection in vitro. Finally, using a complete site-saturation mutagenesis methodology focused on the CDR (complementarity determining regions), a single point mutation (51E7) was identified that improved the 80% plaque reduction neutralization of the virus by greater than 8-fold. These discovery and evolution strategies can be applied to any emerging pathogen or toxin where a causative agent is known.
Rogers
J
J
Verenium Corporation, 4955 Directors Place, San Diego, CA 92121, USA.
Schoepp
R J
RJ
Schröder
O
O
Clements
T L
TL
Holland
T F
TF
Li
J Q
JQ
Li
J
J
Lewis
L M
LM
Dirmeier
R P
RP
Frey
G J
GJ
Tan
X
X
Wong
K
K
Woodnutt
G
G
Keller
M
M
Reed
D S
DS
Kimmel
B E
BE
Tozer
E C
EC
D000818:Animals; D000914:Antibodies, Viral / Q000235:genetics / Q000302:isolation & purification* / Q000627:therapeutic use; D000918:Antibody Specificity / Q000276:immunology; D002522:Chlorocebus aethiops; D021821:Communicable Diseases, Emerging / Q000517:prevention & control / Q000628:therapy*; D019020:Directed Molecular Evolution / Q000379:methods*; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D017354:Point Mutation / Q000276:immunology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D045169:Severe Acute Respiratory Syndrome / Q000517:prevention & control / Q000628:therapy*; D014709:Vero Cells
D000914:Antibodies, Viral