Project 2 - Vanderbilt University
项目 2 - 范德比尔特大学
基本信息
- 批准号:10362732
- 负责人:
- 金额:$ 80.23万
- 依托单位:
- 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:2019-03-20 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AffinityAfricaAnimal ModelAntibodiesAntibody FormationAntigensAntiviral AgentsAsiaAustraliaBindingBiological AssayBiological ProductsBiological Response Modifier TherapyBiological TestingBlood CellsCell LineCellsCessation of lifeChinese Hamster Ovary CellChiropteraClinicClinical ResearchCyclic GMPDevelopmentDomestic AnimalsEpitopesEquus caballusExhibitsExposure toFamilyGTP-Binding ProteinsGoalsHandHendra VirusHenipavirusHenipavirus InfectionsHumanHybridomasImmuneImmunotherapeutic agentInfectionLaboratoriesLeadMediatingMethodsMonoclonal AntibodiesMonoclonal Antibody TherapyNipah VirusOrganismParamyxovirusPatientsPharmacologic SubstancePreparationPreventionProductionProteinsPublic HealthRNA VirusesResearch Project GrantsSeriesSpeedTechnologyTestingTherapeuticTherapeutic antibodiesTreatment EfficacyUniversitiesVaccine AntigenVaccinesViral AntibodiesVirusVirus DiseasesVirus ReplicationWorkZoonosescross reactivityexperimental studygene synthesisglycoprotein Ghigh throughput screeninghuman monoclonal antibodieslead candidatemannext generationnonhuman primatenovelnovel therapeuticspathogenpreclinical developmentpreventprogramsprophylacticreceptor bindingtherapeutic evaluation
项目摘要
Project Summary
The Henipavirus genus of RNA viruses in the family Paramyxoviridae contains five established species.
Henipaviruses are found naturally in bats in Australia and Asia and more recently have been found in Africa,
and they have a wide host range. These zoonotic pathogens can cause severe illness and death in domestic
animals and humans. The prophylactic and therapeutic options for Hendra and Nipah virus infections in man
are limited. Anti-Hendra/Nipah human mAbs are expected to be valuable antiviral therapeutics as
countermeasures to Hendra and Nipah virus disease in humans. Here, we will isolate panels of naturally
occurring human monoclonal antibodies (mAbs) that bind cross-reactively to both Hendra and Nipah virus F or
G proteins and neutralize both viruses. In preliminary experiments, we have isolated some mAbs that exhibit
very high potency in neutralization assays, suggesting they have high potential as prophylactic and therapeutic
molecules for humans. We propose here a series of aims that will contribute significantly to the development
and characterization of such human mAbs reactive to the F and G glycoproteins of Hendra and Nipah virus in
preparation for clinical studies. The work will identify and fully characterize a panel of highly promising
antibodies with the goal of identifying and selecting lead compounds and advancing their preclinical
development. The work is organized in two major Specific Aims: Aim 1) Isolation of human mAbs from patients
previously infected with henipavirus or exposed to henipavirus vaccine antigens. In this Aim, human mAbs will
be identified that recognize epitopes that are conserved across henipaviruses and neutralize those viruses at
low concentration. Blood cells from a subject exposed to Hendra virus equine vaccine will be screened for virus
specific antibodies. These cells will be converted to stable human hybridoma cell lines and subjected to high-
throughput screening to identify Abs that bind to Hendra and Nipah G proteins and functionally inhibit virus
replication. Aim 2: Develop Abs for the treatment of henipavirus infections. Antibodies identified in Aim 1 will be
tested for their broad recognition of conserved epitopes across all henipaviruses and for their ability to
neutralize in culture. Prioritized antibodies then will be tested for therapeutic efficacy in multiple animal models
of infection including nonhuman primates. The leads will be selected, and CHO cell lines will be made by Mapp
Biopharmaceutical for Ab production, in preparation for cGMP manufacture and IND planning. The work
promises to yield a best-in-class antibody preparation for broad and potent activity against henipaviruses that
can be used to treat or prevent human henipavirus infections.
项目摘要
副粘病毒科RNA病毒的亨尼帕病毒属包含五个已建立的物种。
亨尼帕病毒在澳大利亚和亚洲的蝙蝠中自然发现,最近在非洲发现,
它们的宿主范围很广这些人畜共患病原体可导致严重的疾病和死亡,在国内
动物和人类。人类亨德拉病毒和尼帕病毒感染的预防和治疗选择
是有限的。预期抗亨德拉/尼帕人mAb是有价值的抗病毒治疗剂,
人类亨德拉和尼帕病毒病的对策。在这里,我们将隔离面板的自然
与亨德拉和尼帕病毒F交叉反应性结合的人单克隆抗体(mAb),或
G蛋白并中和这两种病毒。在初步实验中,我们已经分离出一些mAb,
在中和试验中具有非常高的效力,表明它们具有很高的预防和治疗潜力
对人类的分子。我们在此提出了一系列目标,这些目标将大大有助于发展
以及在免疫组织化学中对亨德拉病毒和尼帕病毒的F和G糖蛋白反应的这种人mAb的表征。
准备临床研究。这项工作将确定并充分描述一组非常有前途的
目的是鉴定和选择先导化合物,并推进其临床前
发展本工作有两个主要的具体目的:目的1)从患者中分离人单克隆抗体
先前感染过亨尼帕病毒或暴露于亨尼帕病毒疫苗抗原。在该目标中,人mAb将
识别在亨尼帕病毒中保守的表位,并中和这些病毒。
低浓度。将对暴露于亨德拉病毒马疫苗的受试者的血细胞进行病毒筛查
特异性抗体这些细胞将被转化为稳定的人杂交瘤细胞系,并进行高浓度培养。
通过筛选鉴定结合Hendra和Nipah G蛋白并功能性抑制病毒的Ab
复制的目的2:研制抗亨尼帕病毒的抗体。目标1中鉴定的抗体将
测试了它们对所有亨尼帕病毒的保守表位的广泛识别,以及它们对
在培养中中和。然后将在多个动物模型中测试优先化的抗体的治疗功效
包括非人类灵长类动物。将选择先导物,并由Mapp制备CHO细胞系
用于抗体生产的生物制药,为cGMP生产和IND规划做准备。工作
有望产生一种针对亨尼帕病毒具有广泛和有效活性的同类最佳抗体制剂,
可用于治疗或预防人亨尼帕病毒感染。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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James E Crowe其他文献
Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape
呼吸道合胞病毒预防触手可及:疫苗和单克隆抗体的现状
- DOI:
10.1016/s1473-3099(22)00291-2 - 发表时间:
2023-01-01 - 期刊:
- 影响因子:31.000
- 作者:
Natalie I Mazur;Jonne Terstappen;Ranju Baral;Azucena Bardají;Philippe Beutels;Ursula J Buchholz;Cheryl Cohen;James E Crowe;Clare L Cutland;Linda Eckert;Daniel Feikin;Tiffany Fitzpatrick;Youyi Fong;Barney S Graham;Terho Heikkinen;Deborah Higgins;Siddhivinayak Hirve;Keith P Klugman;Leyla Kragten-Tabatabaie;Philippe Lemey;Louis Bont - 通讯作者:
Louis Bont
James E Crowe的其他文献
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{{ truncateString('James E Crowe', 18)}}的其他基金
Human Monoclonal Antibodies for Encephalitic Alphaviruses
脑炎甲病毒的人单克隆抗体
- 批准号:
10539155 - 财政年份:2022
- 资助金额:
$ 80.23万 - 项目类别:
Human Monoclonal Antibodies for Encephalitic Alphaviruses
脑炎甲病毒的人单克隆抗体
- 批准号:
10669266 - 财政年份:2022
- 资助金额:
$ 80.23万 - 项目类别:
Structure based design of trimer interface epitope focused universal influenza vaccines
基于三聚体界面表位的通用流感疫苗的结构设计
- 批准号:
10361516 - 财政年份:2020
- 资助金额:
$ 80.23万 - 项目类别:
Structure based design of trimer interface epitope focused universal influenza vaccines
基于三聚体界面表位的通用流感疫苗的结构设计
- 批准号:
10576343 - 财政年份:2020
- 资助金额:
$ 80.23万 - 项目类别:
B-Cell Epitope Discovery and Mechanisms of Antibody Protection: Genetic and Structural Basis for Virus Neutralization
B 细胞表位发现和抗体保护机制:病毒中和的遗传和结构基础
- 批准号:
10021075 - 财政年份:2019
- 资助金额:
$ 80.23万 - 项目类别:
Research Project 2: Therapeutic Human Monoclonal Antibody Treatments for Filoviruses
研究项目2:丝状病毒的治疗性人单克隆抗体治疗
- 批准号:
10576280 - 财政年份:2019
- 资助金额:
$ 80.23万 - 项目类别:
Functional Antibody Repertoire Against S. aureus Leukocidins after Invasive Human Infection
人类侵袭性感染后针对金黄色葡萄球菌杀白细胞素的功能性抗体库
- 批准号:
10541163 - 财政年份:2019
- 资助金额:
$ 80.23万 - 项目类别:
B-Cell Epitope Discovery and Mechanisms of Antibody Protection: Genetic and Structural Basis for Influenza Neutralization
B 细胞表位发现和抗体保护机制:流感中和的遗传和结构基础
- 批准号:
10669544 - 财政年份:2019
- 资助金额:
$ 80.23万 - 项目类别:
B-Cell Epitope Discovery and Mechanisms of Antibody Protection: Genetic and Structural Basis for Influenza Neutralization
B 细胞表位发现和抗体保护机制:流感中和的遗传和结构基础
- 批准号:
10903692 - 财政年份:2019
- 资助金额:
$ 80.23万 - 项目类别:
Research Project 2: Therapeutic Human Monoclonal Antibody Treatments for Filoviruses
研究项目2:丝状病毒的治疗性人单克隆抗体治疗
- 批准号:
10564151 - 财政年份:2019
- 资助金额:
$ 80.23万 - 项目类别:
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