Specific and Broadly Active Monoclonal Antibody Therapeutics Against The Filoviruses

项目2：概要 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， 严重疾病的爆发和高死亡率。这些病毒的流行潜力是由 2013年至2016年爆发，从一名受感染的幼儿蔓延到多个国家的28，000例病例。没有 治疗性干预措施尚未被批准用于丝状病毒感染，并且仍然迫切需要 有效的治疗。在这次学术和行业合作中，我们将在具体和广泛的领域推进 反应性单克隆抗体（mAb）治疗，我们已经证明，提供完全的保护， 非人类灵长类动物重要的是，这项研究建立在全球合作的结果，病毒性出血 发热免疫联盟（维克），产生了最全面的抗埃博拉病毒数据集 mAb尚未组装。从这项全面的研究中，我们了解到单克隆抗体介导的 保护和建立改进的，多变量计算模型，预测治疗组合， 最大化最强预测体内保护的抗体特征（包括Fc介导的效应子功能， Fc糖型和中和）。其他治疗组合，一种是埃博拉病毒特异性的，一种是广泛的 交叉反应，预测详细的研究可能会提供更大的疗效比两个已经在手。 使用我们的治疗候选物和另外的充分表征的维克单克隆抗体作为对照，我们将评估 保护阈值和标准和创新动物模型之间的保护相关性。在更广泛的 水平，这项研究将阐明如何忠实特定的mAb功能（例如，Fab驱动的中和，物种- 特异性Fc驱动的保护）在用于满足FDA“双动物规则”的动物模型中翻译， 治疗批准。我们将进一步使用创新的高通量技术，标准的基于细胞的测定， 靶向糖型和充分表征的Fc置换文库，以优化Fv和Fc两者，从而增强 保护活动。对于这个项目，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、动物模型体内评价、计算机建模和统计分析，以及 工业mAb生产和开发。我们的转化研究计划是由数据， 比以前任何可用的更全面，将提出优化的治疗候选人， 具有流行潜力的多种病毒，并将有助于建立一个广泛适用的平台来治疗丝状病毒 和其他传染病。

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.