Prophylactic Immunotherapy for Marburg Virus Disease Outbreak Control

控制马尔堡病毒病暴发的预防性免疫治疗

• 批准号: 10697211
• 负责人: M Javad Aman
• 金额: $ 98.62万
• 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: 2023-05-12 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697211
• 关键词: Acceleration; Advanced Development; Africa; African; Aman; Animal Model; Antibodies; Antigens; B-Lymphocytes; Binding; Binding Sites; Biochemical; Biological Availability; Biological Products; Biological Response Modifier Therapy; Blood Chemical Analysis; Bundibugyo virus; Case Fatality Rates; Cavia; Cell Line; Cells; Cessation of life; Chinese Hamster Ovary Cell; Collaborations; Country; Development; Disease Outbreaks; Dose; Drug Kinetics; Ebola; Ebola Hemorrhagic Fever; Ebola virus; Engineering; Epidemic; Epitopes; Exposure to; Family; Fatality rate; Fc domain; Filovirus; Fright; Funding; Future; GP2 gene; GTPBP1 gene; Generations; Genetic; Glycoproteins; Half-Life; Health Personnel; Health protection; Healthcare; Healthcare Systems; Hematology; Hospital Personnel; Human; Immunity; Immunization; Immunotherapy; Infection; Injections; Lead; Left; Licensure; Liquid substance; Macaca; Macaca fascicularis; Marburg Virus Disease; Marburgvirus; Measures; Memory B-Lymphocyte; Modeling; Monitor; Monoclonal Antibodies; Mus; Mutation; Nature; Nurses; Patients; Periodicals; Persons; Phase; Physicians; Prevention; Preventive vaccine; Process; Production; Prophylactic treatment; Research; Research Personnel; Resources; Risk; Safety; Serum; Services; Small Business Innovation Research Grant; Social Workers; Sudan Ebola virus; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Toxicology; Transfection; Vaccinated; Variant; Viral Hemorrhagic Fevers; Viremia; Virus; Work; Zaire Ebola virus; animal efficacy; animal rule; antigen binding; base; cell bank; chimeric antibody; clinical development; drug candidate; efficacy evaluation; efficacy study; epidemic response; experience; first responder; hemorrhagic fever virus; high risk population; innovation; manufacture; mortality; mutant; neonatal Fc receptor; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; novel strategies; outbreak control; pathogen; pressure; product development; prophylactic; rational design; receptor binding; stable cell line; success; therapeutically effective; viral outbreak; Acceleration; Advanced Development; Africa; African; Aman; Animal Model; Antibodies; Antigens; B-Lymphocytes; Binding; Binding Sites; Biochemical; Biological Availability; Biological Products; Biological Response Modifier Therapy; Blood Chemical Analysis; Bundibugyo virus; Case Fatality Rates; Cavia; Cell Line; Cells; Cessation of life; Chinese Hamster Ovary Cell; Collaborations; Country; Development; Disease Outbreaks; Dose; Drug Kinetics; Ebola; Ebola Hemorrhagic Fever; Ebola virus; Engineering; Epidemic; Epitopes; Exposure to; Family; Fatality rate; Fc domain; Filovirus; Fright; Funding; Future; GP2 gene; GTPBP1 gene; Generations; Genetic; Glycoproteins; Half-Life; Health Personnel; Health protection; Healthcare; Healthcare Systems; Hematology; Hospital Personnel; Human; Immunity; Immunization; Immunotherapy; Infection; Injections; Lead; Left; Licensure; Liquid substance; Macaca; Macaca fascicularis; Marburg Virus Disease; Marburgvirus; Measures; Memory B-Lymphocyte; Modeling; Monitor; Monoclonal Antibodies; Mus; Mutation; Nature; Nurses; Patients; Periodicals; Persons; Phase; Physicians; Prevention; Preventive vaccine; Process; Production; Prophylactic treatment; Research; Research Personnel; Resources; Risk; Safety; Serum; Services; Small Business Innovation Research Grant; Social Workers; Sudan Ebola virus; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Toxicology; Transfection; Vaccinated; Variant; Viral Hemorrhagic Fevers; Viremia; Virus; Work; Zaire Ebola virus; animal efficacy; animal rule; antigen binding; base; cell bank; chimeric antibody; clinical development; drug candidate; efficacy evaluation; efficacy study; epidemic response; experience; first responder; hemorrhagic fever virus; high risk population; innovation; manufacture; mortality; mutant; neonatal Fc receptor; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; novel strategies; outbreak control; pathogen; pressure; product development; prophylactic; rational design; receptor binding; stable cell line; success; therapeutically effective; viral outbreak

The ebolaviruses (EBOV, SUDV, BDBV) and marburgviruses (MARV and RAVV), cause periodic outbreaks of severe viral hemorrhagic fever with very high mortality rates. The 2013-2016 Ebola virus disease (EVD) outbreak in West Africa highlighted the serious nature of a filovirus epidemic and its regional and global implications. This outbreak took an enormous toll on people at the front line of the epidemic control, i.e., physicians, nurses, hospital personnel, social workers, and other support staff. Many nurses and physicians lost their lives helping patients and many left their profession out of fear of exposure. The near breakdown of the local healthcare system further fueled the spread of the virus across the region. Therefore, protection of the first responders must be a high priority and is critical for successful outbreak control. Currently, while a prophylactic vaccine is available for EVD, there are no therapeutic or prophylactic countermeasures available for Marburg virus disease (MVD) which has led to many outbreaks and as recently as June 2022. The objective of this proposal is to develop an effective immunoprophylactic for protection of first responders against MVD. Such a product mut be 1) extremely potent to enable economically affordable low dose levels, and 2) have extended bioavailability to provide a reasonably long duration of protection. We and others have isolated several classes of neutralizing monoclonal antibodies (mAbs) for ebolaviruses. However, for marburgviruses only a single class of mAbs against the glycoprotein (GP) has been described that all target a single epitope within the receptor binding site (RBS) of MARV and RAVV GP. Now, using a novel immunization and B cell selection approach with rationally designed antigens we have succeeded in identifying a new class of mAbs that bind to a novel epitope and neutralize marburgviruses at sub- to low-nM concentrations and are up to 100-fold more potent than the RBS binders. A lead antibody, R217, has been selected and shown to protect against MVD in mice, guinea pigs, and nonhuman primates (NHPs). In this SBIR project we propose to engineer the Fc portion of this macaque-human chimeric antibody by introducing mutations (YTE) in the FcRn binding region to extend the half-life of the antibody and evaluate the efficacy of the product. In Aim 1 R217-YTE will be produced in ExpiCHO cells and fully characterized. Pharmacokinetics (PK) will be evaluated in NHPs. In Aim 2, the efficacy of R217-YTE against MVD will be evaluated in the settings of pre- and post-exposure prophylaxis and the required dose level and serum neutralization activity required for protection will be determined. Aim 3 will be focused on generation of a stable manufacturing cell line in CHO cells and a research cell bank to be used for production of future GMP cell banks. If successful, we anticipate further development of the product under DoD or BARDA funding and approval under FDA Animal Rule.

埃博氏病毒（Ebov，Sudv，BDBV）和Marburgviruess（Marv和Ravv），导致定期爆发 严重的病毒出血热，死亡率很高。 2013-2016埃博拉病毒疾病（EVD）暴发 在西非，强调了货洛瓦病毒流行的严肃性质及其区域和全球影响。这 爆发在流行病控制的前线，即医师，护士，医院的前线造成了巨大的损失。 人员，社会工作者和其他支持人员。许多护士和医生丧生，帮助患者 许多人出于担心暴露而抛弃了职业。当地医疗保健系统的近乎分解 加剧了病毒在该地区的传播。因此，对第一响应者的保护必须很高 优先级，对于成功的爆发控制至关重要。目前，虽然可用于预防性疫苗 evd，没有可用于马堡病毒疾病（MVD）的治疗或预防性对策 直到2022年6月，该提议的目的是开发有效的目的 免疫预防剂可保护第一反应者免受MVD的影响。这样的产品mut是1）极有效的 为了实现经济负担得起的低剂量水平，2）具有延长的生物利用度，以提供合理的 长时间的保护时间。我们和其他人已经隔离了几类中和单克隆抗体 （mAb）埃博氏病毒。但是，对于马堡病毒，只有一类MAB针对糖蛋白（GP） 已经描述了所有靶向MARV和RAVV的受体结合位点（RB）中的单个表位 GP。现在，使用新型免疫和B细胞选择方法与合理设计的抗原我们有 成功地识别了与新的表位结合并中和sub-- 低NM浓度，比RBS Binders高达100倍。铅抗体R217具有 被选中并显示以预防小鼠，豚鼠和非人类灵长类动物（NHP）中的MVD。在这个 SBIR项目我们建议通过引入该猕猴 - 人类嵌合抗体的FC部分 FCRN结合区域中的突变（YTE），以扩展抗体的半衰期并评估 产品。在AIM 1中，R217-YTE将在Expicho细胞中产生并充分表征。药代动力学 （PK）将在NHP中进行评估。在AIM 2中，将在设置中评估R217-YTE对MVD的功效 暴露前和暴露后预防以及所需的剂量水平和血清中和活性 将确定保护。 AIM 3将集中于Cho中的稳定制造细胞系的生成 细胞和研究细胞库用于生产未来的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。