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PEDS Advance Access originally published online on May 13, 2008
Protein Engineering Design and Selection 2008 21(8):495-505; doi:10.1093/protein/gzn027
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases

J. Rogers1,{dagger}, R.J. Schoepp2, O. Schröder1,{dagger}, T.L. Clements2, T.F. Holland1,{dagger}, J.Q. Li1,{dagger}, J. Li1,{dagger}, L.M. Lewis1,{dagger}, R.P. Dirmeier1, G.J. Frey1,{dagger}, X. Tan1, K. Wong1,{dagger}, G. Woodnutt1,{dagger}, M. Keller1,{dagger}, D.S. Reed3, B.E. Kimmel1,{dagger} and E.C. Tozer1,4

1 Verenium Corporation, 4955 Directors Place, San Diego, CA 92121 2Diagnostic Systems Division 3Department of Animal Studies, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702, USA

4 To whom correspondence should be addressed. E-mail: eileen.tozer{at}yahoo.com

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 HuFRTM (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.

Keywords: antibody discovery/humanized/optimized/SARS-CoV

Received December 7, 2007; revised April 16, 2008; accepted April 18, 2008.

{dagger} No longer at Verenium


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