Development of broadly neutralizing antibodies to treat hantavirus infections

开发广泛中和抗体来治疗汉坦病毒感染

• 批准号: 10088067
• 负责人: Raymond Alvarez
• 金额: $ 5.5万
• 依托单位: ICHOR BIOLOGICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-03 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088067
• 关键词: Acute; Adult; Alanine; Americas; Animal Model; Antibodies; Antibody Response; Antibody Therapy; Area; Asia; Binding; Biological; Biological Assay; Biotechnology; Bioterrorism; Businesses; Cardiopulmonary; Centers for Disease Control and Prevention (U.S.); Chilean; Chronic; Clinic; Clinical Trials; Communicable Diseases; Computer software; Coupled; Data; Department of Defense; Development; Disease; Disease Outbreaks; Epitopes; Europe; Family; Fever; Funding; Glycoproteins; Goals; Government; Grant; Hantavirus; Hantavirus Infections; Hemorrhagic Fever with Renal Syndrome; Human; Immunoglobulin G; Incidence; Industry; Infection; Kidney Diseases; Knowledge; Lead; Legal; Legal patent; Mediating; Mediation; Mesocricetus auratus; Mutagenesis; Mutation; Patients; Phase; Positioning Attribute; Public Health; Radial; Risk; Rodent; Safety; Sampling; Scanning; Serum; Severities; Small Business Innovation Research Grant; Syndrome; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Travel; Treatment Efficacy; United States National Institutes of Health; Vaccination; Vaccines; Virus; Virus Diseases; base; cohort; commercial application; commercialization; cross reactivity; experimental study; high risk; human monoclonal antibodies; in vivo; in vivo evaluation; infection risk; innovation; interest; molecular modeling; mortality; neutralizing antibody; novel; pathogen; pathogenic virus; pharmacokinetics and pharmacodynamics; phase 1 study; programs; prophylactic; therapeutic development; transmission process; young adult

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.

项目概要 汉坦病毒是一个新兴的高致病性病毒家族，可导致 100-200,000 例两种严重的病例 一年发热病；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，在其他情况下造成 35-40% 的死亡率 健康的年轻人。事实上，由于汉坦病毒的死亡率很高，因此被认为是一种潜在的病毒。 NIH、CDC 和国防部的生物恐怖主义代理。再加上没有的事实 病毒特异性治疗或全球批准的疫苗来预防感染，这些新兴病毒 对全球公共卫生构成相当大的威胁。虽然没有针对病毒的特异性治疗方法，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 患者拥有可以交叉中和异源菌株的抗体。因此，我们 假设一些 HPCS 和 HFRS 恢复期患者进化出可以广泛中和多种抗体的抗体 汉坦病毒株。 Ichor Biologics 开发了一个平台，用于分离天然存在的人类 单克隆抗体 (mAb)，我们已使用它从 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 开发出可识别异源菌株的抗体，这表明某些患者可能拥有可识别异源菌株的抗体 广泛中和多种汉坦病毒株。因此，要开发的产品是一种广泛中和的产品 用于治疗由汉坦病毒感染引起的 HCPS 和 HFRS 的抗体治疗剂。为了检验这个方案的可行性 产品，在目标 1 中，我们将筛选先前从 HCPS 患者中分离出的数百种单克隆抗体 中和多种汉坦病毒株的能力。该屏幕将通过 BSL2 安全、快速的 汉坦病毒中和试验由 Ichor Biologics 开发。由于病毒可以获得突变，从而允许 使它们逃避抗体反应，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，以确定可以组合成治疗鸡尾酒的抗体。这些研究将 确定开发基于汉坦病毒的广泛中和抗体疗法的潜​​力 恢复期患者并加速临床使用的任何治疗方法的商业化。考虑到 生物制品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（例如强大的 科学、法律和商业顾问以及智利政府的资助），我们拥有得天独厚的优势 成功开发并商业化一种广泛中和抗体疗法，用于治疗 HCPS 和 HFRS 由汉坦病毒感染引起。