Broadly Protective Bispecific Antibodies for Treatment of Ebola Virus Disease

 描述(由申请人提供)：埃博拉病毒和马尔堡病毒(Marv)构成丝状病毒科(“丝状病毒”)家族，可引起严重出血热，人类病例死亡率为50%-90%。西非目前的疫情在地理范围和规模上都是史无前例的，突显了继续发展治疗学的必要性。在五种埃博拉病毒中，扎伊尔和苏丹亚型(分别为EBOV和SUDV)致病性最强，均导致反复暴发。1976-2012年间，埃博拉病毒和SUDV合计占埃博拉相关死亡人数的95%以上。此外，另一种埃博拉病毒亚型--本迪布乔病毒(BDBV)在2007年和2012年造成了两次大规模疫情。目前的丝状病毒抗体治疗是狭义的毒株特异性的，因此治疗效果有限。这项提议的目标是利用创新的抗体技术平台-双特异性抗体(Bis-mAb)工程，开发出交叉中和的、有效地对抗EBOV、SUDV和BDBV的治疗性抗体鸡尾酒。我们已经制备了几种能够有效中和EBOV和SUDV的双特异性单抗(Bis-mAbs)，它们与病毒糖蛋白(GP)碱基的关键中和表位结合，以及一系列与多种丝状病毒物种结合的新型交叉反应抗体。值得注意的是，其中一种单抗在EBOV和SUDV小鼠感染模型中都显示出体内保护作用。这是首次报道丝状病毒交叉保护性抗体。我们的初步数据还揭示了丝状病毒GP的糖帽和融合环内的一系列新的、保守的表位。我们假设当Bis-mAbs靶向时，这些关键表位可以以协同的方式被利用。利用靶向多个关键表位所产生的增强的亲和力和协同中和作用，这类双抗将代表一类新型的高效、广泛中和丝状病毒的治疗药物。在目标1中，我们将探索结合GP碱基的Bis-mAb设计，以优化效力，并测试它们与结合糖帽中第二个表位的交叉结合抗体的中和作用。AIM 2将专注于开发新的双链单抗，这些单抗针对存在于多种丝状病毒物种中的新的、高度保守的gp表位。将测试Bis-mAbs对EBOV、SUDV和BDBV的增强和广泛的中和活性，以选择3-5个领先的候选治疗方案。第一阶段的研究将为预期的第二阶段成分奠定基础，在这一阶段中，将评估最有效的双链抗体组合在体内保护的能力。这种方法可以进一步扩展，以创造新型的Bis-mAb鸡尾酒，可以针对包括MARV在内的所有丝状病毒物种。这项工作代表了学术(爱因斯坦)和商业(综合生物治疗)实体之间的合作伙伴关系，以开发交叉中和、治疗性Bis-mAb鸡尾酒。该方法利用了专有抗体、技术平台和双方合作伙伴的互补专业知识。这些疗法将填补一个重大的治疗空白，无法使用传统的抗体分离方法获得。

 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.