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.

项目概要 埃博拉 (EBOV) 和马尔堡 (MARV) 病毒会导致人类和非人类出血热疾病 灵长类动物 (NHP) 的病死率高达 90%。 2013-2016 年埃博拉病毒病 (EVD) 爆发 导致超过28,000例病例和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。这次疫情爆发激发了全球前所未有的努力 开发埃博拉病毒病疫苗和疗法，并获得批准的疫苗和两种单克隆抗体 （单克隆抗体）疗法。重要的是，对 EBOV 单克隆抗体和后来的 SARS-CoV2 单克隆抗体的研究确立了 单克隆抗体鸡尾酒可有效治疗病毒性疾病。与 EVD 相比，治疗方法的开发 尽管马尔堡病毒病 (MVD) 爆发过几次 MVD，其中包括 2022 年的一次，但其发病率一直滞后。 MPI I/II 期快速通道 SBIR 应用的研究人员开发了两类 mAb 靶向药物 MARV 的受体结合位点 (RBS) 和内部融合环 (IFL) 内不重叠的表位 糖蛋白（GP）。 RBS 结合单克隆抗体 (MR186) 主要通过效应器功能提供保护，同时 IFL 结合剂 (R217) 是迄今为止发现的最有效的中和 MARV mAb。 MR186 已 利用 Fc 部分中的 YTE 突变进行工程设计，以增强生物利用度，并在岩藻糖基中生产 转移酶缺陷型 CHO 细胞系可增强效应子功能 (MR186-YTEAF)。目前我们正在推出 YTE 突变至 R217 Fc，生成候选治疗药物 R217-YTE。在这个拟议的项目中，我们 利用这些互补的作用机制来开发这两种单克隆抗体的高效混合物 MVD 治疗。使用单克隆抗体鸡尾酒也有望降低逃逸变异的风险。该提案有四个 具体目标。在目标 1（第一阶段部分）中，R217-YTE 将在 ExpiCHO 细胞中生产并进行全面表征。 该鸡尾酒的卓越功效将在 MARV-Angola 的豚鼠模型中得到证明，这一里程碑 将用于过渡到第二阶段 SBIR。第二阶段部分从目标 2 开始，其中鸡尾酒的功效 将在一系列适应性设计的 NHP 实验中在 NHP 模型中进行测试，最终获得卓越的功效 将通过与单个单克隆抗体的比较来正式证明。在目标 3 中，我们将评估 多项 NHP 功效中抗体血清的药代动力学 (PK) 和药效学 (PD) 研究包括目标 1 中进行的研究。PK/PD 数据与临床结果之间的相关性将是 探索过。目标 4 我们将专注于在 CHO 细胞中生成稳定的生产细胞系，并且至少 每种 mAb 的四个克隆将用于未来的 GMP 细胞库。如果成功的话，我们预计 在 DoD 或 BARDA 资助下进一步开发产品，并根据 FDA 动物规则获得批准。