The Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2419-24. doi: 10.1073/pnas.0914503107. Epub 2010 Feb 1.
Over the past decade, West Nile virus (WNV) has spread to all 48 of the lower United States as well as to parts of Canada, Mexico, the Caribbean, and South America, with outbreaks of neuroinvasive disease occurring annually. At present, no therapeutic or vaccine is available for human use. Epidemics of WNV and other emerging infectious disease threats demand cost-efficient and scalable production technologies that can rapidly transfer effective therapeutics into the clinical setting. We have previously reported that Hu-E16, a humanized anti-WNV mAb, binds to a highly conserved epitope on the envelope protein, blocks viral fusion, and shows promising postexposure therapeutic activity. Herein, we generated a plant-derived Hu-E16 mAb that can be rapidly scaled up for commercial production. Plant Hu-E16 was expressed at high levels within 8 days of infiltration in Nicotiana benthamiana plants and retained high-affinity binding and potent neutralizing activity in vitro against WNV. A single dose of plant Hu-E16 protected mice against WNV-induced mortality even 4 days after infection at rates that were indistinguishable from mammalian-cell-produced Hu-E16. This study demonstrates the efficacy of a plant-produced mAb against a potentially lethal infection several days after exposure in an animal challenge model and provides a proof of principle for the development of plant-derived mAbs as therapy against emerging infectious diseases.
在过去的十年中,西尼罗河病毒(WNV)已经传播到美国所有 48 个州以及加拿大、墨西哥、加勒比海和南美洲的部分地区,每年都会爆发神经侵袭性疾病。目前,尚无针对人类使用的治疗方法或疫苗。WNV 和其他新发传染病威胁的流行需要具有成本效益和可扩展的生产技术,以便能够迅速将有效的治疗方法推向临床应用。我们之前曾报道过,Hu-E16 是一种人源化抗 WNV mAb,可与包膜蛋白上的一个高度保守表位结合,阻止病毒融合,并显示出有希望的暴露后治疗活性。在此,我们生成了一种植物来源的 Hu-E16 mAb,可以快速扩大规模进行商业生产。在 Nicotiana benthamiana 植物中渗透 8 天后,植物 Hu-E16 可高水平表达,并保留了针对 WNV 的体外高亲和力结合和强大的中和活性。单次给予植物 Hu-E16 可保护小鼠免受 WNV 诱导的死亡率,即使在感染后 4 天也能达到与哺乳动物细胞产生的 Hu-E16 相同的效果。这项研究证明了在动物挑战模型中,植物生产的 mAb 在暴露后数天即可有效抵抗潜在致命感染,并为开发植物来源的 mAb 作为针对新发传染病的治疗方法提供了原理验证。