Human monoclonal antibodies for prophylaxis and therapy against the new coronavirus

用于预防和治疗新型冠状病毒的人单克隆抗体

基本信息

批准号：
10265634
负责人：
Michel C Nussenzweig
金额：
$ 45.83万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265634
关键词：
2019-nCoV Advanced Development Antibodies B-Lymphocytes Binding Biological Assay Blood Blood Donations COVID-19 vaccine Cell Separation Cells China Chiroptera Cloning Collaborations Complex Coronavirus Coronavirus spike protein Cryoelectron Microscopy Crystallization Development Diagnostic Disease Disease Outbreaks Ebola Enzyme-Linked Immunosorbent Assay Epitopes Flavivirus Future Goals HIV HIV-1 Health Hepatitis B Virus Human Immunoglobulin G In Vitro Individual Infection Influenza Knowledge Laboratories Letters Light Malaria Medical Membrane Proteins Memory B-Lymphocyte Methods Middle East Respiratory Syndrome Coronavirus Molecular Molecular Conformation Mutation North Carolina Passive Transfer of Immunity Patients Pre-Clinical Model Procedures Prophylactic treatment Protein Binding Domain Proteins Protomer Recombinants Resistance SARS-CoV-2 spike protein Sampling Series Serum Severe Acute Respiratory Syndrome Structure Surface Antigens Techniques Testing Therapeutic Transfection Universities Ursidae Family Vaccine Design Vaccine Therapy Vaccines Variant Virus Washington ZIKA authority coronavirus disease cross reactivity effective therapy experimental study expression vector human monoclonal antibodies in vitro activity in vivo medical countermeasure neutralizing antibody novel coronavirus particle pathogen prevent protein complex protein structure public health emergency receptor binding recruit vaccine development

2019-nCoV Advanced Development Antibodies B-Lymphocytes Binding Biological Assay Blood Blood Donations COVID-19 vaccine Cell Separation Cells China Chiroptera Cloning Collaborations Complex Coronavirus Coronavirus spike protein Cryoelectron Microscopy Crystallization Development Diagnostic Disease Disease Outbreaks Ebola Enzyme-Linked Immunosorbent Assay Epitopes Flavivirus Future Goals HIV HIV-1 Health Hepatitis B Virus Human Immunoglobulin G In Vitro Individual Infection Influenza Knowledge Laboratories Letters Light Malaria Medical Membrane Proteins Memory B-Lymphocyte Methods Middle East Respiratory Syndrome Coronavirus Molecular Molecular Conformation Mutation North Carolina Passive Transfer of Immunity Patients Pre-Clinical Model Procedures Prophylactic treatment Protein Binding Domain Proteins Protomer Recombinants Resistance SARS-CoV-2 spike protein Sampling Series Serum Severe Acute Respiratory Syndrome Structure Surface Antigens Techniques Testing Therapeutic Transfection Universities Ursidae Family Vaccine Design Vaccine Therapy Vaccines Variant Virus Washington ZIKA authority coronavirus disease cross reactivity effective therapy experimental study expression vector human monoclonal antibodies in vitro activity in vivo medical countermeasure neutralizing antibody novel coronavirus particle pathogen prevent protein complex protein structure public health emergency receptor binding recruit vaccine development

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项目摘要

The WHO and US authorities have declared a public health emergency over the recent outbreak of a new coronavirus (CoV) originating from Wuhan, China (nCoV-2019, recently renamed SARS-CoV-2 and responsible for causing the coronavirus disease termed COVID-2019). The discovery of human monoclonal antibodies to this new CoV and obtaining a molecular understanding of its target epitopes will advance the development of diagnostics, therapeutics and vaccines to limit virus spread. The overall goal of this proposal is to discover and characterize potent broadly neutralizing antibodies to nCoV-2019 that also neutralize closely related strains of CoV such as SARS and other variants currently found in bats but likely to be able to produce human infections in the future. The Nussenzweig laboratory has developed robust methods to isolate, recombinantly produce and characterize human antibodies from the memory B cells of individuals infected by a series of different pathogens including HIV-1, Flaviviruses including Zika, and Hepatitis B virus (1, 2). These methods have also been used by other laboratories to isolate neutralizing antibodies to malaria, Ebola, influenza and other human infections (reviewed in (3)). The Bjorkman laboratory has performed structural studies using these antibodies to obtain information that directs vaccine design and therapies (2, 4-23). In Aim 1, we obtain samples from nCoV-2019 convalescing individuals (see letter from Dr. Wesley Van Voorhis). Serum samples will be tested for binding to the trimeric nCoV-2019 spike protein (S) and to the isolated receptor binding domain (RBD) of the S protein (see letter of collaboration from Dr. John Pak at Chan- Zuckerberg Biohub). Individuals with high titers against S and RBD will be recruited for large blood donations. Antibodies will be identified from the memory B cells of these individuals. In Aim 2 we will clone and express the antibodies obtained in Aim 1. The anti-nCoV-2019 antibodies will be tested for binding to the S protein from Severe Acute Respiratory Syndrome (SARS) and other closely related bat-derived CoV to test for cross- reactivity. Any promising antibodies will be evaluated for neutralizing activity (see letter by Dr. Timothy Sheahan at the University of North Carolina). In Aim 3 Dr. Bjorkman will solve crystal structures of antibody Fabs, and cryo-EM structures of coronavirus spike trimers complexed with Fabs from antibodies identified from Aims 1 and 2. In addition to helping guide vaccine development through the identification of neutralizing targets, the proposed discovery of human monoclonal antibodies to nCoV-2019 and related viruses bears a significant translational potential, such as the treatment and prophylaxis of severe medical conditions associated with nCoV-2019 infection by passive antibody transfer.

世卫组织和美国当局在最近爆发的新爆发中宣布了公共卫生紧急冠状病毒（COV）起源于中国武汉（NCOV-2019，最近更名为SARS-COV-2和负责引起冠状病毒疾病，称为COVID-2019）。人类单克隆的发现对这种新COV的抗体并获得对其靶标的姿势的分子理解将推动开发诊断，治疗剂和疫苗以限制病毒扩散。该提案的总体目标是发现并表征有效的广泛中和抗体到NCOV-2019也可以中和紧密相关的COV菌株，例如SARS和其他变体在蝙蝠中发现，但可能能够在将来产生人类感染。 Nussenzweig实验室已经开发了可靠的方法来分离，重组产生和表征人类抗体由一系列不同病原体感染的个体的记忆B细胞，包括HIV-1，黄病毒包括Zika和乙型肝炎病毒（1、2）。这些方法也已被其他实验室使用分离对疟疾，埃博拉病毒，流感和其他人类感染的中和抗体（在（3）中进行了综述）。这 Bjorkman实验室已经使用这些抗体进行了结构研究，以获取指导的信息疫苗设计和疗法（2，4-23）。在AIM 1中，我们从NCOV-2019康复人员那里获取样品（请参阅Wesley博士的来信范·沃尔希斯（Van Voorhis））。血清样品将测试与三聚体NCOV-2019尖峰蛋白结合，并与 S蛋白的孤立受体结合结构域（RBD）（请参阅Chan-的John Pak博士的合作信 Zuckerberg Biohub）。针对S和RBD的滴度高的人将被招募用于大量献血。将从这些个体的记忆B细胞中鉴定抗体。在AIM 2中，我们将克隆并表达在AIM 1中获得的抗体。将测试抗NCOV-2019抗体与S蛋白结合从严重的急性呼吸综合征（SARS）和其他密切相关的蝙蝠衍生的COV来测试交叉反应性。将评估任何有希望的抗体以中和活动的评估（请参阅蒂莫西博士的信北卡罗来纳大学的Sheahan）。在AIM 3 Bjorkman博士将解决抗体的晶体结构 fabs和冠状病毒尖峰三聚体的冷冻EM结构，与鉴定的抗体的晶圆厂复合来自目标1和2。除了通过鉴定中和靶标帮助指导疫苗开发外，提出的针对NCOV-2019和相关病毒的人类单克隆抗体具有重要意义转化潜力，例如严重医疗状况的治疗和预防 NCOV-2019通过被动抗体转移感染。