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

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.

埃博拉病毒（EBOV、SUDV、BDBV）和马尔堡病毒（MARV 和 RAVV）引起定期爆发 严重的病毒性出血热，死亡率非常高。 2013-2016 年埃博拉病毒病 (EVD) 爆发 西非的会议强调了丝状病毒流行的严重性及其区域和全球影响。这 疫情的爆发，给奋战在疫情防控第一线的医生、护士、医院等人员造成了巨大的损失。 人员、社会工作者和其他支持人员。许多护士和医生在帮助病人的过程中丧生 许多人因为害怕暴露而放弃了自己的职业。当地医疗保健系统进一步几近崩溃 加剧了病毒在该地区的传播。因此，必须高度保护第一响应者 优先事项，对于成功控制疫情至关重要。目前，虽然有预防性疫苗 EVD，目前尚无针对马尔堡病毒病 (MVD) 的治疗或预防措施， 已导致多次疫情爆发，最近一次是在 2022 年 6 月。该提案的目标是制定有效的 用于保护急救人员免受 MVD 侵害的免疫预防剂。这样的产品必须是 1) 非常有效 实现经济上可负担的低剂量水平，2) 延长生物利用度以提供合理的 保护持续时间长。我们和其他人分离出了几类中和单克隆抗体 （单克隆抗体）针对埃博拉病毒。然而，对于马尔堡病毒，只有一类针对糖蛋白 (GP) 的单克隆抗体 据描述，所有这些都针对 MARV 和 RAVV 受体结合位点 (RBS) 内的单个表位 全科医生。现在，使用新型免疫和 B 细胞选择方法以及合理设计的抗原，我们获得了 成功鉴定出一类新的单克隆抗体，该单克隆抗体可与新表位结合并中和马尔堡病毒 浓度可达低 nM，且比 RBS 结合剂的效力高出 100 倍。先导抗体 R217 具有 已被选择并证明可以预防小鼠、豚鼠和非人灵长类动物 (NHP) 的 MVD。在这个 SBIR 项目我们建议通过引入来设计这种猕猴-人嵌合抗体的 Fc 部分 FcRn 结合区的突变（YTE），以延长抗体的半衰期并评估疗效 产品。目标 1 R217-YTE 将在 ExpiCHO 细胞中生产并进行全面表征。药代动力学 (PK) 将在 NHP 中进行评估。在目标 2 中，将在以下环境中评估 R217-YTE 对抗 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 保护将被确定。目标 3 将侧重于在 CHO 中生成稳定的生产细胞系 细胞和研究细胞库，用于生产未来的 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。