Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus.
Neutralization 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.
Oliphant
Theodore
T
Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, Missouri 63110, USA.
Engle
Michael
M
Nybakken
Grant E
GE
Doane
Chris
C
Johnson
Syd
S
Huang
Ling
L
Gorlatov
Sergey
S
Mehlhop
Erin
E
Marri
Anantha
A
Chung
Kyung Min
KM
Ebel
Gregory D
GD
Kramer
Laura D
LD
Fremont
Daved H
DH
Diamond
Michael S
MS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D003001:Cloning, Molecular; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009500:Neutralization Tests; D010957:Plasmids / Q000235:genetics; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism; D014901:West Nile Fever / Q000276:immunology / Q000628:therapy*; D014902:West Nile virus / Q000276:immunology*; D015003:Yeasts
D000911:Antibodies, Monoclonal; D017931:DNA Primers; D014759:Viral Envelope Proteins