Monoclonal Antibody Cocktail for Treatment of Marburg Virus Disease

用于治疗马尔堡病毒病的单克隆抗体混合物

• 批准号: 10761372
• 负责人: M Javad Aman
• 金额: $ 29.34万
• 依托单位: ABVACC, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761372
• 关键词: 2019-nCoV; Africa; African; Aman; Angola; Animal Model; Antibodies; Antibody Therapy; Binding; Binding Sites; Biological Availability; Biological Products; Biological Response Modifier Therapy; Blood Chemical Analysis; Case Fatality Rates; Cavia; Cell Line; Cells; Cessation of life; Chinese Hamster Ovary Cell; Clinical; Collaborations; Comparative Study; Complete Blood Count; Data; Development; Disease; Disease Outbreaks; Disease Outcome; Dose; Drug Kinetics; Ebola; Ebola Hemorrhagic Fever; Ebola virus; Engineering; Epitopes; Exhibits; FDA approved; Fatality rate; Filovirus; Fucosyltransferase; Funding; Future; GP2 gene; GTPBP1 gene; Generations; Glycoproteins; Human; Immunotherapy; Individual; Infection; Injections; Lead; Macaca fascicularis; Marburg Virus Disease; Marburgvirus; Measures; Modeling; Monitor; Monoclonal Antibodies; Mutation; Outcome; Pharmacodynamics; Phase; Property; Regression Analysis; Reporting; Research; Research Personnel; Risk Reduction; Sampling Studies; Series; Serum; Small Business Innovation Research Grant; Surface; Survival Analysis; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Transfection; Vaccines; Variant; Viral; Viral Hemorrhagic Fevers; Viremia; Virus; Virus Diseases; Zaire Ebola virus; animal efficacy; animal rule; antibody immunotherapy; base; cell bank; clinical development; design; drug candidate; effective therapy; efficacy evaluation; efficacy study; experimental study; guinea pig model; manufacture; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; pathogen; pharmacokinetics and pharmacodynamics; primary endpoint; product development; protective efficacy; prototype; receptor binding; secondary endpoint; sobriety; stable cell line; success; therapeutic candidate; therapeutic development; therapeutically effective; vaccine development; viral outbreak

Project Summary Ebola (EBOV) and Marburg (MARV) viruses cause hemorrhagic fever disease in humans and nonhuman primates (NHPs) with case-fatality rates as high as 90%. The 2013-2016 Ebola Virus Disease (EVD) outbreak led to over 28,000 cases and 11,000 deaths and took an enormous toll on the economy of West African nations, in the absence of any vaccine or therapeutic options. This outbreak spurred an unprecedented global effort for development of vaccines and therapeutics for EVD and led to an approved vaccine and two monoclonal antibody (mAb) therapeutics. Importantly studies with EBOV mAbs and later SARS-CoV2 mAbs established the value of mAb cocktails for effective treatment of viral diseases. In contrast to EVD, development of therapeutics for Marburg Virus Disease (MVD) has been lagging despite several MVD outbreaks including one in 2022. The investigators on this MPI Phase I/II Fast Track SBIR application have developed two classes of mAbs targeting non-overlapping epitopes within the receptor binding site (RBS) and the internal fusion loop (IFL) of MARV glycoprotein (GP). The RBS-binding mAb (MR186), provides protection primarily through effector functions, while the IFL-binder (R217) is the most potent neutralizing MARV mAb discovered to-date. MR186 has been engineered to enhance bioavailability using YTE mutation in the Fc portion, and produced in a fucosyl- transferase deficient CHO cell line to enhance effector functions (MR186-YTEAF). We are currently introducing YTE mutations into R217 Fc to generate the therapeutic candidate R217-YTE. In this proposed project we harness these complementary mechanisms of action to develop a highly effective cocktail of these two mAbs for MVD treatment. Use of mAb cocktail is also expected to reduce the risk of escape variant. The proposal has four Specific Aims. In Aim 1 (Phase I portion), R217-YTE will be produced in ExpiCHO cells and fully characterized. Superior efficacy of the cocktail will be demonstrated in a guinea pig model of MARV-Angola and this milestone will serve for transition to Phase II SBIR. Phase II Portion starts with Aim 2, in which the efficacy of the cocktail will be tested in NHP models in series of adaptively designed NHP experiments and finally the superior efficacy will be formally demonstrated in comparison with the individual mAbs. In Aim 3 we will evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of the antibodies in sera from a number of NHP efficacy studies including studies performed in Aim 1. Correlations between PK/PD data and clinical outcome will be explored. Aim 4 we will be focused on generation of stable manufacturing cell lines in CHO cells and at lease four clones of each mAb will be produced to be used for future GMP cell banks. If successful, we anticipate further development of the product under DoD or BARDA funding and approval under FDA Animal Rule.

项目摘要 埃博拉病毒（EBOV）和MARBUG（MARV）病毒引起人类和非人类的出血热疾病 案例竞争率高达90％的灵长类动物（NHP）。 2013-2016埃博拉病毒疾病（EVD）暴发 导致超过28,000例和11,000人死亡，并对西非国家的经济造成了巨大损失， 在没有任何疫苗或治疗选择的情况下。这次爆发刺激了前所未有的全球努力 开发EVD的疫苗和治疗剂，并导致批准的疫苗和两种单克隆抗体 （mAb）治疗学。重要的是，对EBOV mAb和后来的SARS-COV2 mAb的研究确定了 MAB鸡尾酒可有效治疗病毒疾病。与EVD相反，用于开发 尽管有几次MVD暴发，包括2022年的一次MVD暴发，但Marburg病毒疾病（MVD）仍在落后。 该MPI I/II阶段的研究人员快速轨道应用程序已开发了两类的mAb靶向 MARV的受体结合位点（RB）和内部融合回路（IFL）内的非重叠表位 糖蛋白（GP）。 RBS结合MAB（MR186），主要通过效应函数提供保护，而 IFL-BINDER（R217）是最有效的中和Marv mab发现的迄今为止。 MR186曾经 设计用于在FC部分使用YTE突变增强生物利用度，并在葡萄糖基中产生 转移酶不足的CHO细胞系可增强效应子功能（MR186-YTEAF）。我们目前正在介绍 YTE突变进入R217 FC，以生成治疗性候选R217-YTE。在这个拟议的项目中，我们 利用这些互补的作用机制，以开发这两个mab的高效鸡尾酒 MVD处理。预计使用MAB鸡尾酒也有望降低逃生变体的风险。该提议有四个 具体目标。在AIM 1（I期部分）中，R217-YTE将在外论细胞中产生并完全表征。 鸡尾酒的卓越功效将在Marv-Angola的豚鼠模型和这个里程碑中展示 将用于过渡到II期SBIR。第二阶段的部分从AIM 2开始，其中鸡尾酒的功效 将在NHP模型中测试一系列自适应设计的NHP实验，最后是优质的功效 将与单个mAb相比，将正式证明。在AIM 3中，我们将评估 来自许多NHP功效的血清中抗体的药代动力学（PK）和药效学（PD） 包括在AIM 1中进行的研究在内的研究。PK/PD数据与临床结果之间的相关性将是 探索。 AIM 4我们将专注于CHO细胞中稳定的生产细胞系的生成 每个MAB的四个克隆将用于未来的GMP细胞库。如果成功，我们预计 根据FDA动物规则，根据国防部或Barda资金的批准进一步开发产品。