title: Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases.
abstract: 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.
authors.affiliation: Verenium Corporation, 4955 Directors Place, San Diego, CA 92121, USA.
authors.forename: J
authors.initials: J
authors.lastname: Rogers
authors.forename: R J
authors.initials: RJ
authors.lastname: Schoepp
authors.forename: O
authors.initials: O
authors.lastname: Schröder
authors.forename: T L
authors.initials: TL
authors.lastname: Clements
authors.forename: T F
authors.initials: TF
authors.lastname: Holland
authors.forename: J Q
authors.initials: JQ
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: L M
authors.initials: LM
authors.lastname: Lewis
authors.forename: R P
authors.initials: RP
authors.lastname: Dirmeier
authors.forename: G J
authors.initials: GJ
authors.lastname: Frey
authors.forename: X
authors.initials: X
authors.lastname: Tan
authors.forename: K
authors.initials: K
authors.lastname: Wong
authors.forename: G
authors.initials: G
authors.lastname: Woodnutt
authors.forename: M
authors.initials: M
authors.lastname: Keller
authors.forename: D S
authors.initials: DS
authors.lastname: Reed
authors.forename: B E
authors.initials: BE
authors.lastname: Kimmel
authors.forename: E C
authors.initials: EC
authors.lastname: Tozer
mesh_terms: 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
chemical_list: D000914:Antibodies, Viral