Protein engineering, design & selection : PEDS · 2008
Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Rogers J, Schoepp R J, Schröder O, Clements T L, Holland T F, Li J Q, Li J, Lewis L M, Dirmeier R P, Frey G J, Tan X, Wong K, Woodnutt G, Keller M, Reed D S, Kimmel B E, Tozer E C
Аннотация
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.