Advancing a Candidate Polyclonal Antibody Therapy for Hantavirus Disease

推进汉坦病毒病候选多克隆抗体疗法

基本信息

批准号：
10211120
负责人：
Jay Williams Hooper
金额：
$ 37.99万
依托单位：
GENEVA FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-18 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10211120
关键词：
Age Andes Virus Animal Model Animal Sources Antibodies Antibody Therapy Artificial Human Chromosomes Biological Assay Biological Response Modifier Therapy Case Fatality Rates Categories Cattle Cell Culture Techniques Chile Clinical Communicable Diseases Cyclic GMP DNA Vaccines Dangerousness Devices Disease Disease Progression Drug Kinetics Endemic Diseases Engineering Etiology FDA approved Genes Goals Hamsters Hantaan virus Hantavirus Hantavirus Pulmonary Syndrome Hemorrhagic Fever with Renal Syndrome Human Immunize Immunoglobulins Immunotherapeutic agent In Vitro Infection Intensive Care Units Jet Injections Knock-out Light Measures Medical Research Mesocricetus auratus Modeling Modernization Morbidity - disease rate National Institute of Allergy and Infectious Disease Needles New Mexico Oryctolagus cuniculus Pathogenicity Patients Persons Pharmaceutical Preparations Phase Phase I Clinical Trials Plasma Preclinical Testing Prevention Procedures Prophylactic treatment Puumala virus Reporting Research Research Institute Respiratory distress Shock Sin Nombre virus Standardization Survivors Sweden Symptoms Technology Testing Therapeutic Toxicity Tests Vaccinated Virus Virus Diseases Zoonoses base convalescent plasma cross reactivity efficacy study human tissue hyperimmunization in vitro activity in vivo lead candidate medical countermeasure neutralizing antibody nonhuman primate novel polyclonal antibody preclinical safety preclinical toxicity prevent priority pathogen prophylactic protective efficacy research and development research clinical testing safety testing stability testing transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT Hantaviruses are the etiological agents of hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). There are no FDA-approved medical countermeasures to prevent or treat these unpredictable zoonotic diseases. Recently, clinicians in Chile demonstrated that convalescent plasma from HPS survivors provided a clinical benefit in HPS patients in a compassionate-use study. However, the paucity of available human plasma containing high-titer neutralizing antibodies against hantaviruses, and other drawbacks to the use of human plasma derived products, makes the use of convalescent plasma as an anti- hantavirus product untenable. We propose to further develop a potent polyclonal antibody anti-hantavirus product using transchromosomal (Tc) bovine technology. This technology overcomes the significant challenges presented by therapies consisting of polyclonal antibodies obtained from human plasma donors or animal sources. SAB’s diversitAb™ platform technology uses cattle carrying knockouts of key bovine antibody heavy light chains genes, and the addition of a Human Artificial Chromosome containing the entire human heavy chain locus and the entire human kappa light chain locus. As partners, SAB and the US Army Medical Research Institute of Infectious Diseases (USAMRIID) have already demonstrated that fully-human IgG purified from plasma collected from the Tc bovines immunized with hantavirus DNA vaccines has potent neutralizing antibody activity in vitro, and is protective in vivo (i.e., Syrian hamster models of lethal HPS disease). Here, we will use our existing hantavirus DNA vaccines and diversitAb™ platform technology to produce a pan-hantavirus polyclonal antibody product under cGMP. We will conduct in vitro neutralization assays to measure potency, and in vivo efficacy studies using established Syrian hamster models of infection and disease. In addition, we will subject the candidate product to stability testing, human tissue cross reactivity testing, pharmacokinetic analysis in nonhuman primates, and a GLP preclinical toxicity study in rabbits. Our goal is to advance a lead candidate anti-hantavirus polyclonal antibody immunotherapeutic product through preclinical testing. At the conclusion of these IND-enabling studies, this candidate anti-hantavirus product will be ready for a Phase 1 clinical trial.

项目概要/摘要汉坦病毒是汉坦病毒肺综合征（HPS）和出血热的病原体肾综合征 (HFRS) 没有 FDA 批准的医学对策来预防或治疗这些疾病。最近，智利的登山者证明，恢复期血浆来自于不可预测的人畜共患疾病。在一项同情使用研究中，HPS 幸存者为 HPS 患者提供了临床益处，但其数量很少。含有针对汉坦病毒和其他病毒的高滴度中和抗体的可用人血浆犹豫不决地使用人血浆衍生产品，使恢复期血浆用作抗我们建议进一步开发强效抗汉坦病毒的多克隆抗体。产品采用转染色体（Tc）牛技术，克服了重大挑战。由从人类血浆捐献者或动物获得的多克隆抗体组成的疗法提供 SAB 的 diversitAb™ 平台技术使用携带关键牛抗体重链敲除的牛。轻链基因，以及添加含有整个人类重链的人类人工染色体 SAB 和美国陆军医疗中心作为合作伙伴，开发了链基因座和整个人类 kappa 轻链基因座。美国传染病研究所 (USAMRIID) 已经证明，全人源 IgG 从用汉坦病毒 DNA 疫苗免疫的 Tc 牛收集的血浆中纯化，具有有效的体外中和抗体活性，并且在体内具有保护作用（即致命 HPS 的叙利亚仓鼠模型）在这里，我们将使用我们现有的汉坦病毒 DNA 疫苗和 diversitAb™ 平台技术来根据cGMP生产泛汉坦病毒多克隆抗体产品，我们将进行体外中和。使用已建立的叙利亚仓鼠感染模型进行效力测定和体内效力研究此外，我们将对候选产品进行稳定性测试、人体组织交叉反应性测试。我们的测试、非人类灵长类动物的药代动力学分析以及兔子的 GLP 临床前毒性研究。目标是通过以下方式推进主要候选抗汉坦病毒多克隆抗体免疫治疗产品在这些 IND 启用研究结束时，该候选抗汉坦病毒产品将进行临床前测试。为一期临床试验做好准备。