Evaluation of fully human Pan-Old World Arenavirus monoclonal antibodies as candidate therapeutics for LCMV infection

全人泛旧世界沙粒病毒单克隆抗体作为 LCMV 感染候选疗法的评估

• 批准号: 8981911
• 负责人: Luis Manuel Branco
• 金额: $ 14.77万
• 依托单位: ZALGEN LABS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8981911
• 关键词: Adverse effects; Africa; Antibodies; Antigens; Antiviral Agents; Arenavirus; Argentina; Aseptic Meningitis; Biological Assay; Categories; Cells; Collection; Cultured Cells; Development; Disease; Epidemiologic Studies; Epitopes; Evaluation; Exhibits; Exposure to; Generations; Glycoproteins; Goals; Health; Human; Immunocompromised Host; In Vitro; Individual; Junin virus; Label; Lassa Fever; Lassa virus; Licensing; Lymphocytic choriomeningitis virus; Monoclonal Antibodies; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Neurologic; Neurologic Manifestations; Old World Arenaviruses; Patients; Pharmaceutical Preparations; Population; Procedures; Public Health; Readiness; Reporting; Ribavirin; Risk; Seroprevalences; Survivors; Testing; Therapeutic; Transplantation; United States; United States Food and Drug Administration; Vaccines; Viral Hemorrhagic Fevers; Virus; Virus Diseases; base; biodefense; combat; cross reactivity; effective therapy; human monoclonal antibodies; in vivo; mortality; mouse model; neglect; nonhuman primate; pathogen; public health relevance; reverse genetics; therapy development

 DESCRIPTION (provided by applicant): Several arenaviruses, chiefly Lassa virus (LASV) in West Africa and Junín virus (JUNV) in the Pampas region of Argentina, cause hemorrhagic fever (HF) disease in humans and pose a serious public health concern in their endemic regions. Thus, LASV is estimated to infect several hundred thousand individuals yearly in its endemic regions of West Africa, resulting in a high number of Lassa fever (LF) cases associated with high morbidity and mortality. Likewise, JUNV causes Argentine HF (AHF), a disease associated with hemorrhagic and neurological manifestations and fatality rates of 15-30%. On the other hand, although the worldwide- distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) does not cause HF, evidence indicates that LCMV is a neglected important human pathogen. Thus, LCMV has been shown to cause a significant number of cases of congenital neurological and ophthalmological diseases. Moreover, LCMV poses a serious threat to immunocompromised individuals as tragically documented recently by fatal cases of LCMV infection associated with patients undergoing transplant procedures. In addition, epidemiological studies have shown a high seroprevalence of LCMV in the United States and other populations tested, raising the question of whether LCMV may contribute to the many cases of undiagnosed aseptic meningitis reported yearly. Besides a public health risk, LCMV poses also a credible biodefense threat and is classified as a Category A priority pathogen by the NIAID. Public health concerns posed by LCMV infection of humans are aggravated by the lack of Food and Drug Administration (FDA)-licensed vaccines and current anti-arenaviral therapy being limited to the off-label use of ribavirin, which is only partially effective and associated with side effects. The significance of LCMV in human health and biodefense readiness, together with the limited existing armamentarium to combat LCMV infections, highlight the importance of developing therapies to treat human LCMV infections resulted from an accidental virus exposure, a potential intentional virus release and/or LCMV infections of immunocompromised individuals. To this end we propose to combine the use of our state-of-the- art LCMV reverse genetics with the access to a unique collection of 120 LASV glycoprotein (GP)-specific human monoclonal antibodies (hMAbs) derived from 17 different LF survivors to identify and characterize hMAbs with broadly neutralizing activity (BNhMAbs) in vivo against GPs of different isolates related to human cases of LCMV-induced disease.

 描述（由适用提供）：西非的几种Arenaville，主要是西非的Lassa病毒（LASV）和阿根廷Pampas地区的Junín病毒（JUNV），引起人类的出血热（HF）疾病，并在其内象区域中引起严重的公共卫生关注。据估计，LASV每年在其西非的内在地区每年感染数十万个人，从而导致大量与高发病率和死亡率相关的LASSA热（LF）病例。同样，JUNV导致阿根廷HF（AHF），一种与出血和神经​​系统表现相关的疾病，死亡率为15-30％。另一方面，尽管全球分布的原型体育症病毒病毒病毒病毒（LCMV）并未引起HF，但证据表明LCMV是被忽视的重要人类病原体。这就是LCMV已显示出大量先天性神经系统和眼科疾病。此外，LCMV对免疫功能低下的个体构成了严重威胁，因为最近与接受移植程序的患者有关的致命性LCMV感染病例所记载。此外，流行病学研究表明，在美国和其他测试的人群中，LCMV的血清阳性率很高，这提出了一个问题，即LCMV是否可能导致许多每年报告的未诊断的临床脑膜炎病例。除了公共卫生的风险外，LCMV还假定了可靠的生物陷入威胁，并被NIAID归类为优先病原体。 LCMV感染人类引起的公共卫生问题是由于缺乏食品药物管理局（FDA）确认的疫苗和当前的抗动脉粥样硬病疗法的限制，仅限于对利巴韦林的标签使用，这仅是部分有效的，并且与副作用相关。 LCMV在人类健康和生物防腐的准备方面的重要性，以及现有的对抗LCMV感染的有限的ARMAMENTARIUM，强调了开发治疗人LCMV感染的疗法的重要性，这是由于意外的意外病毒暴露，潜在的故意病毒释放和/或LCMV感染的Immunocomprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompromprompersed rys造成的重要性。为此，我们建议将最先进的LCMV反向遗传学的使用与获得120个LASV糖蛋白（GP）特定的人类单克隆抗体（HMABS）的独特集合，从而从17种不同的LF生存中识别和表征HMABS的人类隔离（b）互为中含量（b），babs依赖于GG的gps bab，babs的抗体（HMAB）（HMABS）（HMABS）（HMABS）（hmabs）（B） LCMV诱导的疾病病例。