A "Trojan Horse" bispecific antibody strategy for broad filovirus therapeutics

丝状病毒是A类病原体，其引起严重且快速致命的疾病， 人类病死率为30- 90%。2013-2016年西非的疫情， 28，000例病例是由其中一种病原体埃博拉病毒（扎伊尔种，EBOV）引起的， 强调迫切需要针对所有毒性丝状病毒的新对策。单克隆 抗体（mAbs）已经成为最有希望的治疗平台， 预防埃博拉病毒病。然而，大多数mAb和mAb鸡尾酒仅在 对单一丝状病毒具有特异性，因此在由其他丝状病毒引起的暴发中使用有限 具有流行潜力，包括本迪布焦病毒（BDBV）、苏丹病毒（SUDV）和马尔堡病毒 MARV病毒。丝状病毒mAb治疗管道中的主要差距是缺乏广泛的 对多种致病丝状病毒有活性的谱疗法。这项建议 利用创新的技术平台，双特异性抗体工程，沿着 来自学术（Einstein）、政府（USAMRIID/日内瓦）和商业的专有mAb （Integrated Biotherapeutics; Mapp Biophamidol）合作伙伴开发双特异性抗体 （双-mAb）作为交叉保护性丝状病毒抗体疗法。我们采用新的方法 我们的团队最近开发了一种“特洛伊木马”双单克隆抗体，可以捕获病毒颗粒 它们自己“搭便车”进入细胞内体，在那里它靶向关键和高度 保守的病毒表位通常隐藏在抗体中。该双mAb显示出有效的， 在体外广泛中和所有埃博拉病毒，并提供针对EBOV的交叉保护， 小鼠中的SUDV，从而提供了双单抗工程化定位于 具有病毒颗粒的内体可以有效地靶向隔离的表位（Wec等，科学 2016）。此外，这种双mAb作为单一组分具有广泛的保护性，因此避免了免疫缺陷。 制造和发展的障碍，鸡尾酒的单克隆抗体，以前已经显示 需要广泛的丝状病毒保护。为了进一步开发这种治疗性双mAb， 我们将扩大高度保守的外部和内体表位的范围， 是有针对性的。该提案的目标是优化和推进bis-mAbs， 组分、泛埃博拉病毒或泛丝状病毒免疫疗法。

Filoviruses are Category A pathogens which cause a severe and rapidly fatal disease with human case fatality rates of 30-90%. The 2013-2016 epidemic in Western Africa, with over 28,000 cases, was caused by one of these agents, Ebola virus (Zaire species, EBOV), and highlights the urgent need for new countermeasures targeting all virulent filoviruses. Monoclonal antibodies (mAbs) have emerged as the most promising therapeutic platform for treatment and prevention of Ebola virus disease. However, most mAbs and mAb cocktails are narrowly specific for a single filovirus, and are thus of limited use in outbreaks caused by other filoviruses with epidemic potential, including Bundibugyo virus (BDBV), Sudan virus (SUDV), and Marburg virus (MARV). A major gap in the filovirus mAb therapeutic pipeline is the lack of broad- spectrum therapies that are active against multiple disease-causing filoviruses. This proposal leverages an innovative technology platform, bispecific antibody engineering, along with proprietary mAbs from academic (Einstein), government (USAMRIID/Geneva), and commercial (Integrated Biotherapeutics; Mapp Biophamaceutical) partners to develop bispecific antibodies (bis-mAbs) as cross-protective filovirus antibody therapies. We build on a new approach recently developed by our team—a `Trojan Horse' bis-mAb that can coöpt virus particles themselves to `hitch a ride' into cellular endosomes, where it targets crucial and highly conserved viral epitopes that are normally hidden from antibodies. This bis-mAb shows potent, broad neutralization of all ebolaviruses in vitro and provides cross-protection against EBOV and SUDV in mice, thus providing proof-of-concept that bis-mAbs engineered to localize to endosome with viral particles can effectively target sequestered epitopes (Wec et al., Science 2016). Furthermore, this bis-mAb is broadly protective as a single component, thus avoiding the manufacturing and development hurdles of cocktails of mAbs that have been previously shown to be required for broad filovirus protection. To further develop this therapeutic bis-mAb modality, we will expand the range of highly conserved external and endosomal epitopes that are targeted. The goal of this proposal is to optimize and advance bis-mAbs as single component, pan-ebolavirus or pan-filovirus immunotherapies.