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

m102.4（一种人类抗 Hendra 和 Nipah 抗体）的临床前开发

• 批准号: 8452173
• 负责人: Antony S. Dimitrov
• 金额: $ 103.95万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-03 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452173
• 关键词: Adverse event; Aerosols; Animal Model; Animals; Antibodies; Biological; Biological Assay; Categories; Cell Line; Centers for Disease Control and Prevention (U.S.); Cercopithecus pygerythrus; Cessation of life; Characteristics; Chinese Hamster Ovary Cell; Clinical Trials; Collaborations; Cyclic GMP; Data; Development; Disease; Disease Outbreaks; Dose; Drug Kinetics; Encephalitis; Exhibits; Family; Ferrets; Fever; Funding; Future; Goals; Hendra Virus; Henipavirus; Hour; Human; In Vitro; Laboratories; Lead; Livestock; Methods; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Nipah Virus; Oryctolagus cuniculus; Outsourcing; Paramyxoviridae; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Preclinical Testing; Preparation; Procedures; Process; Production; RNA Viruses; Reagent; Regimen; Research; Ribavirin; Safety; Seeds; System; Testing; Therapeutic; Time; Tissues; Toxicology; United States National Institutes of Health; Viral; Virulent; Virus; Virus Diseases; Zoonoses; animal efficacy; base; biothreat; cell bank; cross reactivity; experience; glycoprotein G; human monoclonal antibodies; mortality; nonhuman primate; pre-clinical; prevent; product development; prophylactic; public health relevance; research clinical testing; respiratory

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.

描述（由申请人提供）：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，构成副粘病毒科亨尼帕病毒属。它们是包膜的负义RNA病毒，可在多种动物宿主和人类中引起全身性和致命性疾病。它们被列为生物安全4级（BSL4）病毒，并具有若干特征，例如通过气溶胶传播的能力，这证明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类生物威胁剂是合理的。目前尚无针对NiV或HeV的批准治疗方法，大约75%的病例肯定会死亡。利巴韦林用于治疗HeV和NiV没有效果。我们已经鉴定出一种全人源单克隆抗体m102.4，它能有效中和所有可用的体外NiV和HeV分离物，并提供暴露后保护，使雪貂免受NiV攻击，非洲绿猴（AGM）免受HeV攻击。因此，我们认为m102.4将提供有效的暴露后预防NiV和HeV。我们的目标是生产足够的数量来进行ind支持的药理学、毒理学和疗效研究，作为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；4)确定雪貂和AGM攻击模型的最小保护剂量及其治疗窗口。在资助期结束时，我们将(i)准备一个特征的研究级“预种子”用于制造m102.4主细胞库，（ii）优化适合制造cGMP临床试验材料的开发规模工艺，（iii）制造超过60克的开发级m102.4原料药以进行IND支持药代动力学，毒理学和功效研究，以及（iv）执行上述研究。随后的申请将追求完全cGMP生产，1)主细胞库和2)抗体进行1期临床评估。Profectus BioSciences, Inc.拥有必要的开发和外包专业知识、经验和质量体系，将需要在后续申请中支持这些活动。