Development of broadly neutralizing antibodies to treat hantavirus infections

项目摘要 汉坦病毒是一个新兴的高致病性病毒家族，可引起100- 200，000例两种严重的 发热性疾病一年;汉坦病毒心肺综合征（HCPS）和肾综合征出血热 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，一些汉坦病毒株是特别致命的，造成35-40%的死亡率，否则 健康的年轻人。事实上，由于汉坦病毒的高死亡率， 美国国家卫生研究院、疾病预防控制中心和国防部的生物恐怖主义代理人。再加上事实上， 病毒特异性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重大威胁。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）可以控制人类汉坦病毒感染。研究还表明， 一些HFRS和HCPS患者具有可以交叉中和异源菌株的Ab。因此我们 假设一些HPCS和HFRS恢复期患者进化出可广泛中和多种 汉坦病毒株。Ichor Biologics开发了一个平台，用于分离自然发生的人类 单克隆抗体（mAbs），我们已经用它从一个 HCPS康复期患者队列。在描述这些患者时，我们观察到一些患者 开发了识别异源菌株的Ab，这表明一些患者可能拥有 广泛中和多种汉坦病毒株。因此，待开发的产品是一种广泛中和的 抗汉坦病毒治疗剂，用于治疗汉坦病毒感染引起的HCPS和HFRS。为了研究这一点的可行性， 在目标1中，我们将筛选先前从HCPS患者中分离的数百种mAb， 中和多种汉坦病毒株的能力。该屏幕将通过BSL 2-安全、快速 汉他病毒中和试验由Ichor Biologics开发。由于病毒可以获得突变， 在目标2中，我们将确定任何广泛结合的功能表位， 中和Ab以鉴定可组合成治疗性混合物的Ab。这些研究将 确定从汉坦病毒开发一种广泛中和的基于Ab的治疗药物的潜力 这将有助于提高康复期患者的健康水平，并加速临床使用的任何治疗药物的商业化。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定位（例如， 科学，法律的和商业顾问，以及智利政府的资助），我们处于独特的位置， 成功开发并商业化一种广泛中和抗体治疗剂，用于治疗HCPS和HFRS 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.