Specific and Broadly Active Monoclonal Antibody Therapeutics Against The Filoviruses

针对丝状病毒的特异性且广泛活性的单克隆抗体疗法

• 批准号: 10402338
• 负责人: Erica Ollmann Saphire
• 金额: $ 220.97万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402338
• 关键词: Address; Affect; Africa; Animal Model; Antibodies; Antibody Affinity; Antibody Therapy; Antibody-mediated protection; Biological Assay; Bundibugyo virus; Category A pathogen; Cells; Cessation of life; Characteristics; Collaborations; Communicable Diseases; Complex; Computer Models; Data; Data Set; Databases; Development; Disease; Disease Outbreaks; Ebola Hemorrhagic Fever; Ebola virus; Engineering; Epidemic; Evaluation; Filoviridae Infections; Filovirus; Glycoproteins; Goals; Government; Hand; Human; Immune; Immune response; Immunology; Immunotherapeutic agent; Industrialization; Industry Collaboration; Institution; Libraries; Long-Term Survivors; Machine Learning; Marburgvirus; Mechanics; Mediating; Modification; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutation; National Institute of Allergy and Infectious Disease; Patients; Performance; Resistance; Reston Ebola virus; Specific qualifier value; Statistical Data Interpretation; Structure; Sudan Ebola virus; Survivors; Therapeutic; Therapeutic Intervention; Therapeutic Monoclonal Antibodies; Time; Toddler; Translating; Viral; Viral Hemorrhagic Fevers; Virus; animal rule; antibody test; base; biodefense; chimeric antibody; cross reactivity; efficacious treatment; forest; high throughput technology; immune function; improved; in vitro Assay; in vivo; in vivo evaluation; innovation; monoclonal antibody production; mortality; multidisciplinary; neutralizing antibody; nonhuman primate; novel; predictive modeling; product development; structural biology; therapeutic candidate; translational research program; vaccine candidate; vaccine evaluation; virology

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.

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 具有高死亡率的严重疾病的爆发表明了这些病毒的流行潜力。 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。 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 在这次学术和行业合作中，我们将在具体和广泛方面推进有效的治疗。 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 重要的是，这项研究建立在病毒出血性全球合作的成果之上。 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 尚未组装的单克隆抗体从这项综合研究中，我们了解了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 最大化抗体特征，最有力地预测体内保护（包括 Fc 介导的效应器功能， 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。 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 我们将进一步使用创新的高通量技术、标准的细胞分析、 靶向糖型和特征明确的 Fc 取代文库，以优化 Fv 和 Fc 以增强 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 我们的转化研究计划以以下数据为依据。 比以前任何可用的都更全面，将针对以下情况提出优化的治疗候选药物 多种具有流行潜力的病毒，将有助于建立广泛适用的丝状病毒治疗平台 和其他传染病。