Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases.
Rogers J,
Schoepp RJ,
Schröder O,
Clements TL,
Holland TF,
Li JQ,
Li J,
Lewis LM,
Dirmeier RP,
Frey GJ,
Tan X,
Wong K,
Woodnutt G,
Keller M,
Reed DS,
Kimmel BE,
Tozer EC.
Verenium Corporation, 4955 Directors Place, San Diego, CA 92121, USA.
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.
PMID: 18480090 [PubMed - in process]
PMCID: PMC2461042