Advancing a Candidate Polyclonal Antibody Therapy for Hantavirus Disease

项目总结/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批准的医疗对策来预防或治疗这些疾病。 不可预测的人畜共患病最近，智利的临床医生证明， 在一项同情使用研究中，HPS幸存者为HPS患者提供了临床获益。然而，缺乏 含有抗汉坦病毒的高滴度中和抗体的可用人血浆，以及其他 使用人血浆衍生产品的缺点，使得使用恢复期血浆作为抗- 汉坦病毒产品站不住脚。我们建议进一步开发一种有效的抗汉坦病毒的多克隆抗体 产品使用转染色体（Tc）牛技术。这项技术克服了 通过由从人血浆供体或动物血浆供体获得的多克隆抗体组成的疗法呈现 源SAB的diversitAb™平台技术使用携带关键牛抗体重链基因敲除的牛 轻链基因，并添加含有整个人类重链基因的人类人工染色体。 链基因座和整个人κ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， 从用汉坦病毒DNA疫苗免疫的Tc牛收集的血浆中纯化的具有有效的 在体外中和抗体活性，并且在体内是保护性的（即，致命HPS的叙利亚仓鼠模型 疾病）。在这里，我们将利用现有的汉坦病毒DNA疫苗和diversitAb™平台技术， 在cGMP下生产泛汉坦病毒多克隆抗体产品。我们将进行体外中和 测定效价的试验和使用已建立的叙利亚仓鼠感染模型的体内功效研究 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、 在非人灵长类动物中的药代动力学分析和在兔中的GLP临床前毒性研究。我们 目的是通过以下步骤来开发一种领先的候选抗汉坦病毒多克隆抗体免疫产品： 临床前测试在这些IND使能研究结束时，该候选抗汉坦病毒产品将 准备进行第一阶段临床试验

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.