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

• 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
• 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

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宣布，由于最近爆发的一种新的 来自中国武汉的冠状病毒（CoV）（nCoV-2019，最近更名为SARS-CoV-2， 负责引起冠状病毒疾病称为COVID-2019）。人类单克隆抗体的发现 这种新冠病毒的抗体，并获得其靶表位的分子理解，将推动 开发诊断、治疗和疫苗以限制病毒传播。 该提案的总体目标是发现和表征有效的广泛中和抗体 到nCoV-2019，也中和了密切相关的CoV菌株，如SARS和目前的其他变体 在蝙蝠身上发现，但将来可能会感染人类。Nussenzweig实验室 已经开发出强大的方法来分离，重组生产和表征人抗体， 被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、 包括寨卡病毒和B型肝炎病毒（1，2）。这些方法也被其他实验室用于 分离出抗疟疾、埃博拉病毒、流感和其他人类感染的中和抗体（综述见（3））。的 Bjorkman实验室已经使用这些抗体进行了结构研究，以获得指导 疫苗设计和治疗（2，4-23）。 在目标1中，我们从nCoV-2019康复个体中获得样本（见Wesley博士的信 货车沃里斯）。将检测血清样本与三聚体nCoV-2019刺突蛋白（S）和 分离的S蛋白的受体结合结构域（RBD）（参见Chan， Zuckerberg Biohub）。将招募抗S和RBD滴度高的个体进行大量献血。 将从这些个体的记忆B细胞中鉴定抗体。在目标2中，我们将克隆和表达 在目标1中获得的抗体。将检测抗nCoV-2019抗体与S蛋白的结合 从严重急性呼吸系统综合征（SARS）和其他密切相关的蝙蝠衍生的冠状病毒，以测试交叉- 反应性将评价任何有希望的抗体的中和活性（见Timothy博士的信 北卡罗来纳州大学的Sheahan）。在目标3中，Bjorkman博士将解决抗体的晶体结构 Fab和与来自鉴定的抗体的Fab复合的冠状病毒刺突三聚体的冷冻-EM结构 目标1和2。 除了通过鉴定中和靶点帮助指导疫苗开发外， 针对nCoV-2019和相关病毒的人单克隆抗体的拟议发现具有重大意义。 翻译潜力，如治疗和预防与 通过被动抗体转移感染nCoV-2019。