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

丝状病毒是A类病原体，可引起一种严重且迅速致命的疾病 人间病例死亡率为30%-90%。2013-2016年西非疫情，有超过 28,000例是由其中一种病原体--埃博拉病毒(扎伊尔种，EBOV)引起的，以及 强调迫切需要针对所有毒力丝状病毒的新对策。单克隆 抗体(MAbbs)已成为最有前途的治疗和治疗平台。 预防埃博拉病毒病。然而，大多数单抗和单抗鸡尾酒是狭义的 专用于单一丝状病毒，因此在由其他丝状病毒引起的暴发中使用有限 具有流行潜力的病毒，包括本迪布乔病毒(BDBV)、苏丹病毒(SUDV)和马尔堡 病毒(Marv)。丝状病毒单抗治疗管道中的一个主要缺口是缺乏广泛的- 对多种致病丝状病毒有效的光谱疗法。这项建议 利用创新的技术平台，双特异性抗体工程，以及 来自学术界(爱因斯坦)、政府(USAMRIID/日内瓦)和商界的专有单抗 (集成生物疗法；Mapp Biophamtics)合作开发双特异性抗体 (BIS-mAbs)作为交叉保护性丝状病毒抗体疗法。我们建立在一种新的方法上 我们团队最近开发的一种可以复制病毒颗粒的‘特洛伊木马’双抗 他们自己搭便车进入细胞内体，在那里它的目标是至关重要和高度 保守的病毒表位，通常是对抗体隐藏的。这种双抗显示出很强的， 在体外广泛中和所有埃博拉病毒，并提供对埃博拉病毒和 SUDV在小鼠中的表达，从而提供了双链单抗定位的概念验证 带有病毒颗粒的内体可以有效地靶向隔离的表位(WEC等人，科学 2016)。此外，这种双抗作为单一成分具有广泛的保护性，从而避免了 先前展示的单抗鸡尾酒的制造和开发障碍 广泛的丝状病毒保护所必需的。进一步开发这种治疗性双抗 ，我们将扩大高度保守的外部和内体表位的范围， 都是有针对性的。该方案的目标是将双抗作为单一抗体进行优化和推进。 组份、泛埃博拉病毒或泛丝病毒免疫疗法。

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.