Specific and Broadly Active Monoclonal Antibody Therapeutics Against The Filoviruses

项目2：总结 丝状病毒，包括多种埃博拉病毒和两种马尔堡病毒，已经出现了30多次，导致 严重疾病暴发，死亡率高。这些病毒的流行潜力从以下方面得到了证明 2013-2016年爆发，从一名受感染的幼儿传播到多个国家的2.8万例病例。不是 丝状病毒感染的治疗干预措施尚未获得批准，仍迫切需要 有效的治疗方法。在这一学术和行业合作中，我们将在具体和广泛的方面推进 反应性单抗(MAb)治疗，我们已经证明提供了完全保护 非人灵长类动物。重要的是，这项研究建立在全球合作的结果上，病毒出血性 发热免疫治疗联盟(VIC)，产生了最全面的抗埃博拉病毒数据集 单抗还没组装好。从这项全面的研究中，我们了解到单抗介导的其他相关因素 并建立了改进的多变量计算模型，预测治疗组合 最大化最能预测体内保护的抗体特征(包括Fc介导的效应器功能， Fc糖型和中和)。其他治疗组合，一个针对埃博拉病毒，另一个针对埃博拉病毒 这项详细研究预测的交叉反应可能会比现有的两种方法提供更大的疗效。 使用我们的候选治疗方法和其他特性良好的VIC单抗作为对照，我们将评估 标准动物模型和创新动物模型的保护阈值和保护相关性。在更广泛的层面上 水平，这项研究将阐明忠实的特定单抗特征(例如，Fab驱动的中和，物种- 特定的FC驱动的保护)跨动物模型进行转换，以满足FDA对 治疗批准。我们将进一步使用创新的高通量技术，基于标准细胞的检测， 靶向糖型和特征良好的Fc取代物库，以优化Fv和Fc以增强 防护性活动。为了这个项目，我们聘请了一个多学科的结构生物学专家团队， 病毒学、免疫学、动物模型体内评估、计算机建模和统计分析，以及 工业单抗的生产和发展。我们的翻译研究计划由以下数据提供信息 比以往任何产品都更全面，将针对以下问题提出优化的候选治疗方案 具有流行潜力的多种病毒，将有助于建立一个广泛适用的治疗丝状病毒的平台 以及其他传染病。

Project 2: SUMMARY The filoviruses, including multiple ebolaviruses and two marburgviruses, have emerged over 30 times to cause outbreaks of severe disease with high mortality. The epidemic potential of these viruses is demonstrated by the 2013-2016 outbreak, which spread from a single infected toddler to 28,000 cases across multiple nations. No therapeutic interventions are yet approved for filovirus infections, and there remains an urgent need for efficacious treatments. In this academic and industry collaboration, we will advance both specific- and broadly reactive monoclonal antibody (mAb) treatments that we have already shown to provide complete protection in non-human primates. Importantly, this study builds upon results of a global collaboration, the Viral Hemorrhagic Fever Immunotherapeutic Consortium (VIC), that yielded the most comprehensive dataset for anti-Ebola virus mAbs yet assembled. From that comprehensive study, we learned additional correlates of mAb-mediated protection and built improved, multivariate computational models, which predict treatment combinations that maximize antibody features that most strongly predict in vivo protection (including Fc-mediated effector functions, Fc glycoforms, and neutralization). Additional treatment combinations, one Ebola virus-specific and one broadly cross-reactive, predicted by that detailed study may offer even greater efficacy than the two already in hand. Using our therapeutic candidates and additional well-characterized VIC mAbs as controls, we will evaluate thresholds of protection and correlates of protection across standard and innovative animal models. On a broader level, this study will illuminate how faithfully particular mAb features (e.g., Fab-driven neutralization, species- specific Fc-driven protection) translate across animal models used to satisfy the FDA “two-animal rule” for therapeutic approval. We will further use innovative high-throughput technologies, standard cell-based assays, targeted glycoforms and a library of well-characterized Fc substitutions to optimize both Fv and Fc to enhance protective activity. For this project, we have engaged a multidisciplinary team of experts in structural biology, virology, immunology, in vivo evaluation in animal models, computer modeling and statistical analysis, and industrial mAb production and development. Our translational research program is informed by data that are more comprehensive than any previously available, will forward optimized therapeutic candidates against multiple viruses with epidemic potential, and will help establish a broadly applicable platform to treat filoviruses and other infectious diseases.