Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus.
Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus.
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开发具有针对西尼罗河病毒的治疗潜力的人源化单克隆抗体。
DOI：
10.1038/nm1240
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发表时间：
2005-05
期刊：
影响因子：
82.9
通讯作者：
Diamond, Michael S
中科院分区：
文献类型：
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作者：
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
体内西尼罗河病毒（WNV）的中和与针对病毒包膜（E）蛋白的抗体应答的发展相关。使用随机诱变和酵母表面展示，我们定义了14个新产生的单克隆抗体对结构域III的WNV E蛋白的个别接触残基。单克隆抗体，强烈中和西尼罗河病毒定位到一个表面补丁的侧面域III。从WNV感染中恢复的个体的恢复期抗体也检测到了该表位。一种单克隆抗体E16在体外中和了10种不同的菌株，并在小鼠中显示出治疗效果，即使在感染后5天单次给药。产生保留抗原特异性、亲合力和中和活性的人源化形式的E16。在小鼠中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，因此可能是针对人类WNV感染的可行治疗选择。本文的在线版本（doi：10.1038/nm 1240）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1038/nm1240) contains supplementary material, which is available to authorized users.