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

 描述(申请人提供)：几种阿拉伯病毒，主要是西非的拉萨病毒(LASV)和阿根廷潘帕斯地区的Junín病毒(JUNV)，在人类中引起出血热(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，在西非的流行地区，LASV每年感染数十万人，导致与高发病率和高死亡率相关的大量拉沙热(LF)病例。同样，JUNV导致阿根廷心衰(AHF)，这是一种与出血性和神经表现相关的疾病，死亡率为15%-30%。另一方面，尽管世界范围内分布的原型性淋巴细胞性脉络膜脑膜炎病毒(LCMV)不会引起HF，但有证据表明LCMV是一种被忽视的人类重要病原体。因此，LCMV已被证明会导致相当数量的先天性神经和眼科疾病。此外，LCMV对免疫功能低下的人构成严重威胁，最近与移植手术患者相关的LCMV感染致死病例悲剧性地记录了这一点。此外，流行病学研究表明，在美国和其他接受测试的人群中，LCMV的血清阳性率很高，这引发了人们的疑问，即LCMV是否与每年报告的许多未诊断的无菌性脑膜炎病例有关。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，以及当前的抗ArenaVirus治疗仅限于标签外使用利巴韦林，这只是部分有效的，并与副作用相关，加剧了对人类LCMV感染引起的公共卫生问题。LCMV在人类健康和生物防御准备方面的重要性，以及现有抗击LCMV感染的有限设施，突显了开发治疗因意外接触病毒、潜在的故意病毒释放和/或免疫受损个体的LCMV感染而导致的人类LCMV感染的重要性。为此，我们建议结合使用我们最先进的LCMV反向遗传学，并获得来自17个不同LF幸存者的120个LASV糖蛋白(GP)特异性人类单抗(HMAbs)的独特集合，以在体内识别和表征与LCMV诱导的疾病相关的不同分离株的Gp具有广泛中和活性的hMAb(BNhMAbs)。

 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.