Broadly Protective Bispecific Antibodies for Treatment of Ebola Virus Disease

 描述（由申请方提供）：埃博拉病毒和马尔堡病毒（MARV）构成丝状病毒科（“丝状病毒”），可引起严重出血热，人类病死率为50- 90%。西非目前的流行病在地理范围和规模上都是前所未有的，突出表明继续需要开发治疗方法。在五种埃博拉病毒中，扎伊尔和苏丹亚型（分别为EBOV和SUDV）是致病性最强的，两者都导致反复爆发。从1976年到2012年，EBOV和SUDV共同占埃博拉相关死亡的95%以上。此外，另一种埃博拉病毒亚型本迪布焦病毒（BDBV）在2007年和2012年引起了两次大规模的爆发。目前的丝状病毒抗体疗法是狭窄的毒株特异性的，因此具有有限的治疗效用。该提案的目标是使用创新的抗体技术平台，双特异性抗体（Bis-mAb）工程，开发有效对抗EBOV，SUDV和BDBV的交叉中和，治疗性抗体鸡尾酒。我们已经产生了几种可以有效中和EBOV和SUDV的双特异性单克隆抗体（Bis-mAb），其结合病毒糖蛋白（GP）碱基处的关键中和表位，以及一套结合多种丝状病毒物种的新型交叉反应性抗体。值得注意的是，这些mAb之一在EBOV和SUDV鼠感染模型中都显示出体内保护作用。这是丝状病毒交叉保护性抗体的首次报道。我们的初步数据还揭示了一系列新的，保守的表位内的多糖帽和融合环的丝状病毒GP。我们假设，这些关键表位可以利用在一个协同的方式时，靶向双单克隆抗体。利用由靶向多个关键表位产生的增强的亲合力和协同中和，此类Bis-mAb将代表一类新型的高效、广泛中和的丝状病毒治疗剂。在目的1中，我们将探索GP碱基结合双mAb设计以优化效力，并测试它们与接合聚糖帽中的第二表位的交叉结合抗体组合的中和。目标2将专注于开发新型双单抗，其靶向存在于多种丝状病毒物种中的GP上的新的高度保守表位。将测试Bis-mAb针对EBOV、SUDV和BDBV的增强的和广泛的中和活性，以选择3-5种领先的治疗候选物。I期研究将为预期的II期部分奠定基础，其中将评估最有效的Bis-mAb组合的体内保护能力。这种方法可以进一步扩展以产生可以靶向包括MARV在内的所有丝状病毒物种的新型双mAb混合物。这项工作代表了学术（Einstein）和商业（Integrated BioTherapeutics）实体之间的伙伴关系，以开发交叉中和，治疗性的Bis-mAb鸡尾酒。该方法利用了双方的专有抗体、技术平台和互补专业知识。这些疗法将填补一个主要的治疗空白，并且不能使用常规抗体分离方法获得。

 DESCRIPTION (provided by applicant): The ebolaviruses and Marburg virus (MARV) constitute the family Filoviridae ("filoviruses") that cause severe hemorrhagic fever with human case fatalities of 50-90%. The current epidemic in West Africa, unprecedented in terms of geographic scope and size, highlights the continued need for development of therapeutics. Among the five ebolavirus species, the Zaire and Sudan subtypes (EBOV and SUDV, respectively) are the most pathogenic and both have resulted in recurring outbreaks. Together, EBOV and SUDV accounted for over 95% of Ebola-related deaths from 1976-2012. In addition, another ebolavirus subtype, the Bundibugyo virus (BDBV), has caused two sizable outbreaks in 2007 and 2012. Current filovirus antibody therapies are narrowly strain specific, and therefore have limited therapeutic utility. The goal of this proposal is to use an innovative antibody technology platform, bispecific antibody (Bis-mAb) engineering, to develop cross-neutralizing, therapeutic antibody cocktails effective against EBOV, SUDV, and BDBV. We have produced several bispecific monoclonal antibodies (Bis-mAbs) that can effectively neutralize EBOV and SUDV, binding to a critical neutralization epitope at the viral glycoprotein (GP) base, as well as a suite of novel cross-reactive antibodies binding multiple filovirus species. Notably, one of these mAbs has shown in vivo protection in both EBOV and SUDV murine infection models. This is the first report of a filovirus cross-protective antibody. Our preliminary data also reveal a series of novel, conserved epitopes within the glycan cap and the fusion loop of filovirus GP. We hypothesize that these key epitopes can be exploited in a synergistic manner when targeted by Bis-mAbs. Taking advantage of the enhanced avidity and synergistic neutralization that result from targeting multiple key epitopes, such Bis-mAbs will represent a novel class of highly effective, broadly neutralizing filovirus therapeutics. In Aim 1, we will explore GP base binding Bis-mAb designs to optimize potency, and test them for neutralization in combination with a cross-binding antibody that engages a second epitope in the glycan cap. Aim 2 will focus on developing novel Bis-mAbs that target new, highly conserved epitopes on GP that are present in multiple filovirus species. The Bis-mAbs will be tested for enhanced and broad neutralizing activity against EBOV, SUDV, and BDBV to select 3-5 lead therapeutic candidates. Phase I studies will lay the foundation for the anticipated Phase II component, in which the most potent combinations of Bis-mAbs will be evaluated for their ability to protect in vivo. This approach can further be extended to create novel Bis-mAb cocktails that can target all filovirus species including MARV. This work represents a partnership between academic (Einstein) and commercial (Integrated BioTherapeutics) entities to develop cross-neutralizing, therapeutic Bis-mAb cocktails. The approach leverages proprietary antibodies, technology platforms, and complementary expertise from both partners. These therapies will fill a major therapeutic gap and could not be obtained using conventional antibody isolation methods.