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：
9976978
负责人：
Jay Williams Hooper
金额：
$ 104.98万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976978
关键词：
Age Andes Virus Animal Model Animal Sources Antibodies Antibody Therapy Biological Assay Biological Response Modifier Therapy Case Fatality Rates Categories Cattle Cell Culture Techniques Chile Chromosomes, Artificial, Human 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 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.

项目摘要/摘要汉坦病毒是汉坦病毒肺综合征（HPS）和出血热的病因。肾脏综合征（HFRS）。没有FDA批准的医学对策来预防或治疗这些不可预测的人畜共患病。最近，智利的临床医生证明了来自 HPS幸存者在一项富有同情心的研究中为HPS患者提供了临床益处。但是，稀少可用的人血浆中含有高滴度的中和抗体的抗体，其他使用人血浆衍生产品的缺点使使用康复等离子体作为抗汉坦病毒产品站不住脚。我们建议进一步开发潜在的多克隆抗体抗汉坦病毒使用染色体（TC）牛技术的产品。这项技术克服了重大挑战由由人血浆供体或动物获得的多克隆抗体组成的疗法提出来源。 SAB的Diversitab™平台技术使用牛携带的牛群钥匙抗体重物轻链基因，以及含有整个人类重物的人造染色体的添加连锁基因座和整个人类Kappa轻链基因座。作为合作伙伴，SAB和美国陆军医疗传染病研究所（USAMRIID）已经证明了完全人类IgG 从用汉坦病毒DNA疫苗免疫的TC牛的血浆纯化具有有效性在体外中和抗体活性，并在体内受到保护（即，叙利亚仓鼠的致命HPS模型疾病）。在这里，我们将使用现有的Hantavirus DNA疫苗和Diversitab™平台技术来进行在CGMP下产生泛汉塔病毒多克隆抗体产物。我们将进行体外中和使用已建立的叙利亚仓鼠感染模型测量效力和体内效率研究的测定和疾病。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，非人类隐私中的药代动力学分析以及兔子中的GLP临床前毒性研究。我们的目标是通过通过临床前测试。在这些辅助研究的结论时，该候选抗大麻病毒产品将准备进行1期临床试验。