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: 8261688
• 负责人: Antony S. Dimitrov
• 金额: $ 109.78万
• 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/8261688
• 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. 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.

描述（由申请人提供）：Nipah病毒（NIV）和Hendra病毒（HEV）是密切相关的病毒人畜共患病，在paramyxoviridae家族中形成了HENIPAVIRUS属。它们是包裹的，负性的RNA病毒，在各种动物宿主和人类中引起全身性疾病。它们被归类为生物安全级别-4（BSL4）病毒，并具有多种特征，例如通过气溶胶传输的能力将其列表证明其列表为C类Biothreat剂，NIH和CDC是合理的。目前尚无针对NIV或HEV的批准治疗药，并且死亡肯定是75％的病例。利巴韦林已被用于HEV和NIV，无效。我们已经确定了一种完全人类的单克隆抗体M102.4，该抗体在体外有效中和所有可用的NIV和HEV分离株，并在HEV挑战中提供了雪貂的暴露后保护和非洲绿色猴子（AGM）。因此，我们认为M102.4将对NIV和HEV提供有效的暴露后预防性。我们的目的是生产足够的数量来进行临床前开发的必要步骤，以执行辅助药理学，毒理学和有效性研究。我们计划通过以下特定目标来追求目标：1）为M102.4开发分析表征方法； 2）制造M102.4; 3）进行临床前毒理学和药代动力学研究； 4）在雪貂和AGM挑战模型中确定最小的保护剂量及其治疗窗口。 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)执行了研究。随后的应用程序将全面生产1）主细胞库和2）1阶段临床评估的抗体。 Profectus Biosciences，Inc。拥有必要的开发和外包专业知识，经验和质量系统，以支持随后的申请中提出的这些活动。 公共卫生相关性：Nipah病毒（NIV）和Hendra病毒（HEV）是密切相关的病毒动物，与动物和人类的发病率和死亡率显着相关。它们被NIH和CDC列为C类生物治疗剂，因为它们可以与自然储层中隔离，在一般实验室条件下很容易在细胞系中生长至大量的细胞，并通过气溶胶传播。最近的暴发表明，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。目前尚无预防或治疗NIV或HEV感染的批准产品。一种抗HEV和NIV人类单克隆抗体M102.4在2种动物模型中对NIV或HEV的挑战产生了完全保护，其中一种是非人类的灵长类动物。通过此应用，我们打算进行安全性测试，并确定两种动物模型中的功效给药团。在制造抗体产品的同时，我们将生产出特征的研究级“预播”细胞系，用于生产M102.4主细胞库，并开发QA/QC方法，用于抗体表征，纯化，身份和稳定性，适合于生产未来的CGMP临床试验材料。