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.

项目摘要 汉坦病毒是一个新兴的高度致病病毒家族，导致100-200,000例严重 每年发热疾病；汉坦病毒心肺综合征（HCP）和肾脏的出血热 综合征（HFRS）。与其他病毒相比，年度感染的年发病率相对较低 感染，一些汉坦病毒菌株特别致命，导致35-40％的死亡率否则 健康的年轻人。实际上，由于其高死亡率，汉坦病毒被认为是潜在的 NIH，CDC和国防部的生物恐怖主义代理。再加上没有 病毒特异性治疗或全球批准的疫苗以防止感染，这些新兴病毒 代表了对全球公共卫生的巨大威胁。虽然没有病毒特异性治疗，但证据 表明中和抗体（ABS）可以控制人类的汉坦病毒感染。研究还表明 一些HFR和HCPS患者拥有的ABS可以使异源菌株交叉中和。因此，我们 假设某些HPC和HFRS康复患者进化了ABS，可以广泛中和多个 汉坦病毒菌株。 Ichor Biologics已开发了一个平台，用于隔离自然人类的人类 单克隆ABS（mAb），我们用来将几百个汉坦病毒特异性mAb与A分离 HCPS康复患者队列。在表征这些患者时，我们观察到一些患者 开发了识别出异源菌株的ABS，表明某些患者可能拥有ABS 广泛中和多个汉坦病毒菌株。因此，要开发的产品是广泛中和的 AB（S）治疗由汉塔病毒感染引起的HCP和HFR的治疗方法。检查此的可行性 产品，在AIM 1中，我们将筛选以前从HCPS患者中分离出的数百个mAB 中和多个汉坦病毒菌株的能力。该屏幕将通过BSL2-SAFE快速促进 Ichor Biologics开发的汉塔病毒中和测定法。由于病毒可以获取允许的突变 他们逃避了AB的反应，在AIM 2中，我们将确定任何广泛限制的功能表位 中和腹肌以识别可以合并成治疗性鸡尾酒的ABS。这些研究会 确定从汉坦病毒开发广泛中和基于AB的治疗的潜力 康复患者并加速了在诊所使用的任何治疗方法的商业化。考虑 生物制剂的高安全性和功效概况，以及我们在汉坦病毒空间中的强大定位（例如 科学，法律和商业顾问以及智利政府的资金），我们独特地位于 成功地开发和商业化广泛中和的AB治疗方法来治疗HCP和HFRS 由汉坦病毒感染引起。