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

描述（由申请方提供）：尼帕病毒（NiV）和亨德拉病毒（HeV）是形成副粘病毒科亨帕病毒属的密切相关的病毒性人畜共患病。它们是有包膜的负义RNA病毒，在多种动物宿主和人类中引起全身性和致命性疾病。它们被归类为生物安全4级（BSL 4）病毒，并具有几个特征，例如通过气溶胶传播的能力，这证明它们被NIH和CDC列为C类生物威胁剂。目前还没有针对NiV或HeV的批准治疗方法，大约75%的病例肯定会死亡。利巴韦林已被用于对抗HeV和NiV，但没有效果。我们已经鉴定了一种完全人源单克隆抗体m102.4，其在体外有效地中和所有可用的NiV和HeV分离株，并为雪貂提供暴露后保护，使其免受NiV攻击，并为非洲绿色猴（AGM）提供暴露后保护，使其免受HeV攻击。因此，我们认为m102.4将提供针对NiV和HeV的有效暴露后预防。我们的目标是生产足够的数量，以进行IND支持性药理学、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实现我们的目标：1）开发m102.4的分析表征方法; 2）生产m102.4; 3）进行临床前毒理学和药代动力学研究; 4）确定雪貂和AGM攻毒模型中的最小保护剂量及其治疗窗口。到资助期结束时，我们将（i）制备用于生产m102.4主细胞库的表征研究级“预种子”，（ii）优化适用于生产cGMP临床试验材料的开发规模工艺，（iii）生产超过60克开发级m102.4原料药，以进行IND支持性药代动力学，毒理学，和功效研究，以及（iv）执行所述研究。后续申请将追求1）主细胞库和2）用于1期临床评价的抗体的完整cGMP生产。Profectus BioSciences，Inc.具备必要的开发和外包专业知识、经验和质量体系，以支持后续申请中提出的这些活动。 公共卫生相关性：尼帕病毒（NiV）和亨德拉病毒（HeV）是密切相关的病毒性人畜共患病，与动物和人类的显著发病率和死亡率相关。它们被NIH和CDC列为C类生物威胁剂，因为它们可以从天然储库中分离出来，在一般实验室条件下容易在细胞系中大量生长，并通过气溶胶传播。最近的疫情表明，这些病毒具有高度毒性和致命性：HeV和NiV感染导致75%的病例死亡。目前还没有批准的产品可以预防或治疗NiV或HeV感染。抗HeV和NiV人单克隆抗体m102.4在2种动物模型中对NiV或HeV的攻击产生完全保护，其中一种是非人灵长类动物。通过本申请，我们打算进行临床前安全性测试，并确定两种动物模型中的有效性给药方案。在生产抗体产品的同时，我们将生产一种表征的研究级“预接种”细胞系，用于生产m102.4主细胞库，并开发适用于未来cGMP临床试验材料生产的抗体表征、纯化、鉴别和稳定性的QA/QC方法。

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.