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Project II: Biologics Engineering and Antibody Mechanism of Action

项目二：生物制剂工程与抗体作用机制

基本信息

批准号：
10088393
负责人：
Kartik Chandran
金额：
$ 166.21万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-14 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088393
关键词：
Advanced Development Affinity Africa Amino Acid Substitution Amino Acids Animal Model Antibodies Antibody Therapy Antigen-Antibody Complex Antigens B-Lymphocytes Binding Biologic Development Biological Biological Assay Blocking Antibodies Bunyaviridae Case Fatality Rates Category A pathogen Cell Separation Collaborations Crimean-Congo Hemorrhagic Fever Virus Cryoelectron Microscopy DNA Data Development Disease Disease Outbreaks Ebola Hemorrhagic Fever Ebola virus Engineering Epidemic Epitope Mapping Epitopes Escape Mutant Family Family member Fc domain Filovirus Future Gap Junctions Generations Glycoproteins Group Structure Hantavirus Health Hemorrhage Human Immune Immunoglobulin G Immunotherapeutic agent In Vitro Infection Investigation Kinetics Label Lead Link Measures Mediating Medical Molecular Monoclonal Antibodies National Institute of Allergy and Infectious Disease Orthobunyavirus Play Process Production Protein Engineering Proteins Public Health Reagent Recombinants Role Serum Severity of illness Structure Survivors System Therapeutic Translational Research Viral Viral Antigens Viral Hemorrhagic Fevers Virus Virus Diseases Work X-Ray Crystallography antigen binding assay development austin base experience experimental study glycosylation group competition high throughput screening human monoclonal antibodies improved in vivo in vivo evaluation lead candidate medical countermeasure member neutralizing monoclonal antibodies nonhuman primate novel particle pathogen prophylactic protective efficacy recombinant virus screening synergism therapeutic candidate tool

项目摘要

The rapid discovery of human monoclonal antibodies (mAbs) that arise during natural viral infection is central to the Prometheus consortium for developing immunoprophylactic and therapeutic medical countermeasures (MCMs). Our Center of Excellence for Translational Research will focus on developing MCMs for three groups of NIAID Category A priority pathogens (ebolaviruses, Crimean-Congo hemorrhagic fever virus, and hantaviruses). Ebolaviruses, members of the family Filoviridae, cause severe hemorrhagic fever in humans and non-human primates, with human case-fatality rates of up to 90%. As demonstrated by the 2013– 2016 epidemic of Ebola virus disease in West Africa, ebolaviruses pose a significant public health threat. Crimean-Congo hemorrhagic fever virus is a member of the Bunyaviridae family and induces fatal hemorrhaging in up to 50% of human infections. Hantaviruses also belong to the Bunyaviridae family, and infections are associated with over 150,000 cases of disease annually with case-fatality rates >30%. Given the disease severity caused by these viruses, MCMs are urgently needed. The protective efficacy of hyperimmune serum in animal models and humans strongly suggests that human infection and disease by these groups of viruses will be amenable to treatment with mAb-based therapeutics and prophylactics. Project II will facilitate mAb discovery efforts in Project I via the development of molecular tools (Aim 1) required to isolate and characterize candidate therapeutic mAbs from human survivors. Our focus will be on the generation of novel recombinant antigens and BSL-2 viral surrogates to use as probes in single B- cell sorting experiments. These biologics are also vital to the characterization process (Aim 2) that will define mAb epitopes, competition groups, structures, and mechanisms of action, as well as future product assay development in Core B. The data generated by Project II, combined with potency and synergy data from Project I, will allow for a streamlined and mechanistically informed down-selection of the most promising candidate mAbs and mAb combinations for in depth Fc-effector function analyses and optimization (Aim 3) prior to in vivo evaluation of leads by Core C. Project II will also be involved in finalizing the optimal lead immunoprophylactic mAbs to advance in Project III and immunotherapeutic mAbs to enter advanced development within Core B.

在自然病毒感染过程中产生的人单克隆抗体的快速发现，感染是普罗米修斯联盟开发免疫预防和治疗性医疗对策（MCM）。我们的卓越翻译中心研究将侧重于为NIAID A类优先级的三组开发MCM 病原体（埃博拉病毒、克里米亚-刚果出血热病毒和汉坦病毒）。埃博拉病毒是丝状病毒科的成员，在人类中引起严重的出血热，非人类灵长类动物，人类病死率高达90%。正如2013年所示， 2016年埃博拉病毒病在西非流行，埃博拉病毒对公共卫生构成重大威胁威胁克里米亚-刚果出血热病毒是布尼亚病毒科的成员，在高达50%的人类感染中诱导致命的复发。汉坦病毒也属于布尼亚病毒科，感染与每年超过15万例疾病有关病死率> 30%。鉴于这些病毒引起的疾病严重程度，迫切需要。超免疫血清在动物模型和人体中的保护作用较强这表明，人类感染和疾病的这些群体的病毒将受到使用基于mAb的治疗剂和预防剂进行治疗。项目II将促进mAb发现通过开发分离和鉴定所需的分子工具（目标1），表征来自人类幸存者的候选治疗性mAb。我们的重点将放在产生新的重组抗原和BSL-2病毒替代物，用作单个B- 细胞分选实验。这些生物制剂对表征过程（目标2）也至关重要，将定义单克隆抗体表位，竞争组，结构和作用机制，以及未来核心B中的产品测定开发。项目II生成的数据，结合效价和来自项目I的协同数据，将允许简化和机械地知情的向下选择用于深入Fc效应子功能的最有前途的候选mAb和mAb组合在Core C对电极导线进行体内评价之前进行分析和优化（目标3）。项目二还将参与最后确定最佳的先导免疫预防性mAb，以推进项目III，免疫球蛋白mAb进入核心B的高级开发阶段。