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Intramuscular Delivery of Replicon RNA Encoding ZIKV-117 Human Monoclonal Antibody Protects against Zika Virus Infection.
Molecular Therapy - Methods & Clinical Development ( IF 4.7 ) Pub Date : 2020-06-18 , DOI: 10.1016/j.omtm.2020.06.011
Jesse H Erasmus 1, 2, 3 , Jacob Archer 1, 2, 3 , Jasmine Fuerte-Stone 1 , Amit P Khandhar 1, 2 , Emily Voigt 1 , Brian Granger 1 , Robin G Bombardi 4 , Jennifer Govero 5 , Qing Tan 5 , Lorellin A Durnell 5 , Rhea N Coler 1 , Michael S Diamond 5, 6, 7 , James E Crowe 4, 8, 9 , Steven G Reed 1, 2 , Larissa B Thackray 5 , Robert H Carnahan 4, 8 , Neal Van Hoeven 1
Affiliation  

Monoclonal antibody (mAb) therapeutics are an effective modality for the treatment of infectious, autoimmune, and cancer-related diseases. However, the discovery, development, and manufacturing processes are complex, resource-consuming activities that preclude the rapid deployment of mAbs in outbreaks of emerging infectious diseases. Given recent advances in nucleic acid delivery technology, it is now possible to deliver exogenous mRNA encoding mAbs for in situ expression following intravenous (i.v.) infusion of lipid nanoparticle-encapsulated mRNA. However, the requirement for i.v. administration limits the application to settings where infusion is an option, increasing the cost of treatment. As an alternative strategy, and to enable intramuscular (IM) administration of mRNA-encoded mAbs, we describe a nanostructured lipid carrier for delivery of an alphavirus replicon encoding a previously described highly neutralizing human mAb, ZIKV-117. Using a lethal Zika virus challenge model in mice, our studies show robust protection following alphavirus-driven expression of ZIKV-117 mRNA when given by IM administration as pre-exposure prophylaxis or post-exposure therapy.



中文翻译:

肌内传递编码ZIKV-117人单克隆抗体的复制子RNA可以抵抗Zika病毒感染。

单克隆抗体(mAb)治疗剂是治疗传染性,自身免疫性和癌症相关疾病的有效方法。但是,发现,开发和制造过程是复杂的,消耗资源的活动,因此无法在出现的传染病爆发中迅速部署mAb。鉴于核酸递送技术的最新进展,现在有可能就地递送编码mAb的外源mRNA静脉内(iv)输注脂质纳米颗粒包裹的mRNA后的蛋白表达。但是,静脉给药的要求将应用限制在可以选择输液的场合,从而增加了治疗成本。作为一种替代策略,为了使肌内(IM)施用mRNA编码的单克隆抗体,我们描述了一种纳米结构脂质载体,用于递送编码先前描述的高度中和的人类单克隆抗体ZIKV-117的甲病毒复制子。通过在小鼠中使用致命的寨卡病毒攻击模型,我们的研究表明,当通过IM给药作为暴露前预防或暴露后治疗给予α病毒驱动的ZIKV-117 mRNA表达后,其具有强大的保护作用。

更新日期:2020-07-13
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