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

 描述（由申请方提供）：几种沙粒病毒，主要是西非的拉沙病毒（LASV）和阿根廷潘帕斯草原地区的胡宁病毒（JUNV），可引起人类出血热（HF）疾病，并在其流行地区造成严重的公共卫生问题。因此，据估计，LASV每年在其西非流行地区感染数十万人，导致与高发病率和死亡率相关的大量拉沙热（LF）病例。同样，JUNV导致阿根廷HF（AHF），这是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，尽管世界范围分布的原型沙粒病毒淋巴细胞性脉络丛脑膜炎病毒（LCMV）不会引起HF，但证据表明LCMV是一种被忽视的重要人类病原体。因此，LCMV已被证明会导致大量先天性神经和眼科疾病。此外，LCMV对免疫功能低下的个体构成严重威胁，正如最近与接受移植手术的患者相关的LCMV感染的致命病例所记录的那样。此外，流行病学研究表明，在美国和其他受检人群中，LCMV的血清阳性率很高，这就提出了一个问题，即LCMV是否可能导致每年报告的许多未确诊的无菌性脑膜炎病例。除了公共卫生风险外，LCMV还构成可信的生物防御威胁，并被NIAID列为A类优先病原体。由于缺乏食品和药物管理局（FDA）许可的疫苗以及目前的抗沙粒病毒疗法仅限于利巴韦林的标签外使用，LCMV感染引起的人类公共卫生问题加剧，利巴韦林仅部分有效并伴有副作用。LCMV在人类健康和生物防御准备中的重要性，以及有限的现有医疗设备来对抗LCMV感染，突出了开发治疗由意外病毒暴露、潜在故意病毒释放和/或免疫功能低下个体的LCMV感染引起的人类LCMV感染的疗法的重要性。为此，我们建议联合收割机结合使用我们最先进的LCMV反向遗传学与获得来自17种不同LF幸存者的120种LASV糖蛋白（GP）特异性人单克隆抗体（hMAb）的独特集合，以鉴定和表征具有体内广泛中和活性的hMAb（BNhMAb），以对抗与LCMV诱导的人类疾病病例相关的不同分离株的GP。

 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.