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，已出现 30 多次，导致 严重疾病暴发，死亡率高。这些病毒的流行潜力由 2013-2016 年爆发，从一个受感染的幼儿到多个国家的 28,000 例病例。否 针对丝状病毒感染的治疗干预措施尚未获得批准，并且仍然迫切需要 有效的治疗。在这次学术和行业合作中，我们将推进具体和广泛的合作 我们已经证明反应性单克隆抗体 (mAb) 治疗可以提供全面的保护 非人类灵长类动物。重要的是，这项研究建立在全球合作的成果基础上，即病毒性出血性 发烧免疫治疗联盟 (VIC)，产生了最全面的抗埃博拉病毒数据集 单克隆抗体尚未组装。从这项综合研究中，我们了解到单克隆抗体介导的其他相关性 保护并建立了改进的多变量计算模型，该模型可以预测治疗组合 最大化最能预测体内保护的抗体特征（包括 Fc 介导的效应子功能， Fc 糖型和中和）。其他治疗组合，一种针对埃博拉病毒，另一种广泛 这项详细研究预测的交叉反应可能比现有的两种方法具有更大的功效。 使用我们的候选治疗药物和其他特性良好的 VIC mAb 作为对照，我们将评估 标准和创新动物模型的保护阈值和保护相关性。在更广泛的 在水平上，这项研究将阐明特定 mAb 特征（例如 Fab 驱动的中和、物种- 特定的 Fc 驱动的保护）可在用于满足 FDA“双动物规则”的动物模型中进行转化 治疗批准。我们将进一步使用创新的高通量技术、标准的基于细胞的检测、 靶向糖型和特征明确的 Fc 取代文库，以优化 Fv 和 Fc 以增强 保护活动。对于这个项目，我们聘请了结构生物学多学科专家团队， 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 工业单克隆抗体生产和开发。我们的转化研究计划基于以下数据： 比以前任何可用的都更全面，将针对针对的优化候选治疗方案 多种具有流行潜力的病毒，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.