Oliphant Theodore, Engle Michael, Nybakken Grant E, Doane Chris, Johnson Syd, Huang Ling, Gorlatov Sergey, Mehlhop Erin, Marri Anantha, Chung Kyung Min, Ebel Gregory D, Kramer Laura D, Fremont Daved H, Diamond Michael S
Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, Missouri 63110, USA.
Nat Med. 2005 May;11(5):522-30. doi: 10.1038/nm1240. Epub 2005 Apr 24.
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.
西尼罗河病毒（WNV）在体内的中和作用与针对病毒包膜（E）蛋白的抗体反应的发展相关。利用随机诱变和酵母表面展示技术，我们确定了14种新产生的针对WNV E蛋白结构域III的单克隆抗体的各个接触残基。强烈中和WNV的单克隆抗体定位于结构域III侧面的一个表面斑块上。从WNV感染中康复的个体的恢复期抗体也检测到了这个表位。一种单克隆抗体E16在体外中和了10种不同的毒株，并且在小鼠中显示出治疗效果，即使在感染后5天以单剂量给药也是如此。产生了一种保留抗原特异性、亲和力和中和活性的人源化E16。在小鼠的暴露后治疗试验中，单剂量的人源化E16保护小鼠免受WNV诱导的死亡，因此可能是治疗人类WNV感染的一个可行选择。
