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.

自然病毒期间出现的人类单克隆抗体（mAb）的快速发现感染是普罗米修斯联盟的核心，用于发展免疫预防和治疗医学对策（MCMS）。我们的翻译卓越中心研究将着重于为三组NIAID类别开发MCM的优先级病原体（埃博氏病毒，克里米亚 - 隆戈出血热病毒和汉坦病毒）。埃博氏病毒，家庭成员，引起人类严重的出血热和非人类隐私，人类案例率高达90％。如2013年– 2016年西非埃博拉病毒疾病流行病，埃博拉病毒构成了重要的公共卫生威胁。 Crimean-Congo出血热病毒是Bunyaviridae家族的成员，在多达50％的人类感染中诱导致命出血。汉坦病毒也属于 Bunyaviridae家族和感染与每年超过15万例疾病有关案件效率> 30％。考虑到这些病毒引起的疾病严重程度，MCM是迫切需要。动物模型和人类中高免疫血清的保护效率强烈表明这些病毒群的人类感染和疾病将适合基于mAb的治疗和预防药物的治疗。项目第二项目将促进MAB发现通过开发分子工具的开发（AIM 1）来隔离和表征来自人类生存的候选疗法mAB。我们的重点将放在新型重组抗原和BSL-2病毒替代物的产生，用于单个B-的探针细胞分类实验。这些生物制剂对表征过程也至关重要（目标2）将定义mAb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I的协同数据将允许简化且机械通知的下调最有前途的候选MAB和MAB组合的深度FC效应功能分析和优化（AIM 3）在体内评估铅的体内C.项目II还将参与最终确定最佳铅免疫原性mAB，以进步项目III和免疫治疗mABS将在核心B中输入高级发展。