Nature Medicine
11, 522 - 530 (2005)
Published online: 24 April 2005; | doi:10.1038/nm1240
Development of a humanized monoclonal antibody with therapeutic potential against West Nile virusTheodore Oliphant1, Michael Engle2, Grant E Nybakken3, Chris Doane2, Syd Johnson4, Ling Huang4, Sergey Gorlatov4, Erin Mehlhop3, Anantha Marri2, Kyung Min Chung2, Gregory D Ebel5, Laura D Kramer5, Daved H Fremont3
& Michael S Diamond1, 2, 31
Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, Missouri
63110, USA. 2
Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, Missouri
63110, USA. 3
Department of Pathology & Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, Missouri
63110, USA. 4
MacroGenics, 1500 East Guide Drive, Rockville, Maryland
20850, USA. 5
Wadsworth Center, New York State Department of Health, 5668 State Farm Road, Slingerlands, New York
12159, USA.
Correspondence should be addressed to Michael S Diamond diamond@borcim.wustl.eduNeutralization of West Nile virus (WNV) in vivo correlates with the development of an antibody response against the viral envelope (E) protein. Using random mutagenesis and yeast surface display, we defined individual contact residues of 14 newly generated monoclonal antibodies against domain III of the WNV E protein. Monoclonal antibodies that strongly neutralized WNV localized to a surface patch on the lateral face of domain III. Convalescent antibodies from individuals who had recovered from WNV infection also detected this epitope. One monoclonal antibody, E16, neutralized 10 different strains in vitro, and showed therapeutic efficacy in mice, even when administered as a single dose 5 d after infection. A humanized version of E16 was generated that retained antigen specificity, avidity and neutralizing activity. In postexposure therapeutic trials in mice, a single dose of humanized E16 protected mice against WNV-induced mortality, and may therefore be a viable treatment option against WNV infection in humans.
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