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）引起周期性暴发