Development of broadly neutralizing antibodies to treat hantavirus infections

项目总结 汉坦病毒是一种新出现的高致病性病毒家族，可导致100-20万例两种严重的 一年温病；汉坦病毒心肺综合征(HCPS)和肾出血热 综合征(HFRS)。虽然与其他病毒相比，每年的感染发生率相对较低 感染，一些汉坦病毒株特别致命，在其他情况下导致35-40%的死亡率 健康的年轻人。事实上，由于汉坦病毒的高死亡率，它们被认为是一种潜在的 美国国立卫生研究院、疾控中心和国防部的生物恐怖主义特工。再加上这个事实，没有 针对病毒的治疗或全球批准的疫苗以防止感染，这些新出现的病毒 对全球公共卫生构成相当大的威胁。虽然没有针对病毒的治疗方法，但有证据表明 表明中和抗体(Abs)可以控制人类感染汉坦病毒。研究还表明， 一些HFRS和HCPS患者拥有能够交叉中和异源毒株的抗体。因此，我们 假设一些HPCS和HFRS恢复期患者进化出能广泛中和多发性硬化的抗体 汉坦病毒株。Ichor Biologics开发了一个分离自然产生的人类的平台 单抗(MAbs)，我们已经用它从一种病毒中分离出数百株汉坦病毒特异性mAb。 HCPS康复期患者队列。在描述这些患者的特征时，我们观察到一些患者 开发出能够识别异源菌株的抗体，这表明一些患者可能拥有 广泛中和多种汉坦病毒株。因此，要开发的产品是一种广泛的中和 AB(S)治疗汉坦病毒感染引起的猪瘟和肾综合征出血热。为了研究这一点的可行性 产品，在目标1中，我们将对先前从HCPS患者中分离的数百株单抗进行筛选 中和多种汉坦病毒株的能力。此屏幕将由BSL2提供便利-安全、快速 Ichor Biologics开发的汉坦病毒中和试验。因为病毒可以获得突变，从而使 为了逃避抗体反应，在目标2中，我们将确定任何广泛结合的功能表位 中和抗体，以便识别可以组合成治疗鸡尾酒的抗体。这些研究将 确定开发广泛中和汉坦病毒抗体治疗药物的潜力 并加速任何用于临床的治疗药物的商业化。考虑 生物制剂的高安全性和有效性，加上我们在汉坦病毒领域的强大地位(例如Strong 科学、法律和商业顾问，以及智利政府资助)，我们独特的地理位置 治疗猪瘟和肾综合征出血热的广谱中和抗体(S)研制成功并商业化 由汉坦病毒感染引起。

PROJECT SUMMARY Hantaviruses are an emerging family of highly pathogenic viruses that cause 100-200,000 cases of two severe febrile illnesses a year; Hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS). While the annual incidence of infections are relatively low compared to other viral infections, some hantavirus strains are particularly deadly, causing a 35-40% mortality rate in otherwise healthy young adults. In fact, because of their high mortality rates hantaviruses are considered a potential bioterrorism agent by the NIH, CDC and the Department of Defense. Coupled with the fact that there is no virus-specific treatment or globally approved vaccine to protect against infections, these emerging viruses represent a considerable threat to global public health. While there is no virus-specific treatment, evidence indicates that neutralizing antibodies (Abs) can control hantavirus infections in humans. Studies also show that some HFRS and HCPS patients possess Abs that can cross-neutralize heterologous strains. Thus, we hypothesize that some HPCS and HFRS convalescent patients evolve Abs that can broadly neutralize multiple hantavirus strains. Ichor Biologics has developed a platform for the isolation of naturally-occurring human monoclonal Abs (mAbs), which we have used to isolate several hundred hantavirus-specific mAbs from a cohort of HCPS convalescent patients. In characterizing these patients, we observed that some patients developed Abs that recognized a heterologous strain, suggesting that some patients may possess Abs that broadly neutralize multiple hantavirus strains. Therefore, the Product to be developed is a broadly neutralizing Ab(s) therapeutic to treat HCPS and HFRS caused by hantavirus infections. To examine the feasibility of this product, in aim 1 we will screen the hundreds of mAbs previously isolated from HCPS patients for their capacity to neutralize multiple hantavirus strains. This screen will be facilitated by a BSL2-safe, rapid hantavirus neutralization assay developed by Ichor Biologics. Since viruses can acquire mutations that allow them to evade Ab responses, in aim 2, we will determine the functional epitopes bound by any broadly neutralizing Abs in order to identify the Abs that can be combined into a therapeutic cocktail. These studies will determine the potential for developing a broadly neutralizing Ab-based therapeutic from hantavirus convalescent patients and accelerate the commercialization of any therapeutic for use in the clinic. Considering the high safety and efficacy profiles of biologics, plus our strong positioning in the hantavirus space (e.g. strong scientific, legal and business advisors, and Chilean government funding), we are uniquely situated to successfully develop and commercialize a broadly neutralizing Ab(s) therapeutic to treat HCPS and HFRS caused by hantavirus infections.