Preclinical Development of m102.4, a Human Anti-Hendra and Nipah Antibody

描述(申请人提供)：尼帕病毒(NIV)和亨德拉病毒(HEV)是副粘病毒科中形成亨尼帕病毒属的密切相关的人畜共患病。它们是有包膜的负义RNA病毒，会在各种动物宿主和人类中引起一种系统性和致命性疾病。它们被归类为生物安全级别4(BSL4)病毒，并具有几个特征，例如通过气雾剂传播的能力，这证明它们有理由被NIH和CDC列为C类生物制剂。目前还没有针对新城疫或戊型肝炎病毒的已获批准的治疗方法，大约75%的病例肯定会死亡。利巴韦林已被用于治疗HEV和NIV，但没有效果。我们已经鉴定出一种全人单抗m102.4，它能在体外有效中和所有可用的新城疫和戊型肝炎病毒分离株，并在暴露后保护雪貂免受新城疫病毒的攻击，并保护非洲绿猴(AGM)免受戊型肝炎病毒的攻击。因此，我们认为m102.4可以有效地预防新城疫和戊型肝炎病毒感染。我们在这里的目标是生产足够的数量来进行支持IND的药理学、毒理学和疗效研究，作为其临床前开发的必要步骤。我们计划通过以下具体目标来实现我们的目标：1)开发m102.4的分析表征方法；2)制造m102.4；3)进行临床前毒理学和药代动力学研究；以及4)在雪貂和AGM攻击模型中确定最小保护量及其治疗窗口。到资助期结束时，我们将(I)准备好用于制造m102.4主细胞库的特征性研究级“预种子”，(Ii)优化适合制造cGMP临床试验材料的开发规模流程，(Iii)制造超过60克的开发级m102.4药物物质以进行Ind支持性药代动力学、毒理学和疗效研究，以及(Iv)执行上述研究。随后的应用将全面生产cGMP 1)主细胞库和2)抗体，用于1期临床评估。普罗韦克图斯生物科学公司拥有必要的开发和外包专业知识、经验和质量体系，这将是支持在后续应用中提出的这些活动所需的。 公共卫生相关性：尼帕病毒(Niv)和亨德拉病毒(HEV)是密切相关的人畜共患病，在动物和人类中都与显著的发病率和死亡率有关。它们被美国国立卫生研究院和美国疾病控制与预防中心列为C类生物制剂，因为它们可以从它们的天然储存库中分离出来，在一般实验室条件下很容易在细胞系中大量生长，并通过气溶胶传播。最近的暴发表明，这些病毒具有高度的毒性和致命性：75%的病例是由HEV和NIV感染导致死亡的。目前还没有批准的产品来预防或治疗新城疫或戊型肝炎病毒感染。抗HEV和NIV的人源单抗m102.4在2种动物模型(其中一种是非人灵长类动物)上对NIV或HEV的攻击具有完全保护作用。通过这一应用，我们打算在两种动物模型上进行安全性的临床前测试，并确定有效的给药方案。在制造抗体产品的同时，我们将生产一种用于制造m102.4主细胞库的特征化研究级“预种子”细胞系，并为抗体的表征、纯化、鉴定和稳定性开发QA/QC方法，适用于未来cGMP临床试验材料的生产。

DESCRIPTION (provided by applicant): Nipah virus (NiV) and Hendra virus (HeV) are closely related viral zoonoses that form the genus Henipavirus in the family Paramyxoviridae. They are enveloped, negative-sense RNA viruses that cause a systemic and fatal disease in a variety of animal hosts and in humans. They are classified as biological safety level-4 (BSL4) viruses and possess several characteristics, such as the ability to be transmitted via aerosol that justifies their listing as Category C biothreat agents by the NIH and CDC. There is currently no approved therapeutics against either NiV or HeV and death is certain for approximately 75% of the cases. Ribavirin has been used against HeV and NiV with no effect. We have identified a fully human monoclonal antibody, m102.4, that potently neutralizes all available NiV and HeV isolates in vitro and provided post-exposure protection of ferrets from NiV challenge and of African Green Monkeys (AGM) from HeV challenge. We believe that m102.4 would, therefore, provide an effective post-exposure prophylactic against both NiV and HeV. Our objective here is to produce sufficient quantities to perform IND-supportive pharmacology, toxicology and efficacy studies as necessary steps in its preclinical development. We plan to pursue our objective through the following specific aims: 1) Develop analytical characterization methods for m102.4; 2) Manufacture m102.4; 3) Perform preclinical toxicology and pharmacokinetic studies; and 4) Determine the minimal protective dose and its therapeutic window in ferret and AGM challenge models. By the end of the funding period, we will have (i) prepared a characterized research-grade "pre-seed" for use to manufacture a m102.4 Master Cell Bank, (ii) optimized a development-scale process suitable for the manufacturing of cGMP clinical trial materials, (iii) manufactured more than 60 grams of development-grade m102.4 drug substance to perform IND supportive pharmacokinetic, toxicology, and efficacy studies, and (iv) executed said studies. Subsequent applications will pursue full cGMP manufacture of 1) a master cell bank and 2) antibody for Phase 1 clinical evaluation. Profectus BioSciences, Inc. has the necessary development and outsourcing expertise, experience and quality systems in place that will be needed to support these activities proposed under subsequent applications. Public Health Relevance: Nipah virus (NiV) and Hendra virus (HeV) are closely related viral zoonoses that are associated with significant morbidity and mortality in both animals and humans. They are listed as Category C biothreat agents by the NIH and CDC, because they can be isolated from their natural reservoir, easily grown to large amounts in cell lines under general laboratory conditions, and transmitted via aerosol. Recent outbreaks indicate that the viruses are highly virulent and lethal: HeV and NiV infections lead to death in 75% of the cases. There are currently no approved products that prevent or treat NiV or HeV infections. An anti- HeV and NiV human monoclonal antibody, m102.4, has engendered complete protection from challenge with either of NiV or HeV in 2 animal models, one of which is non-human primate. With this application we intend to carry on preclinical testing for safety and determine an efficacy administration regiment in both animal models. While manufacturing of the antibody product, we will produce a characterized research-grade "pre-seed" cell line for use to manufacture m102.4 Master Cell Bank and develop QA/QC methods for the antibody characterization, purification, identity and stability suitable for the manufacturing of future cGMP clinical trial material.