RP3: Therapeutics Human Monoclonal Antibody Treatments for Filoviruses

RP3：丝状病毒的人单克隆抗体治疗

• 批准号: 8814174
• 负责人: James E Crowe
• 金额: $ 171.19万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814174
• 关键词: Aerosols; Affinity; Anaphylaxis; Antibodies; Antibody Repertoire; Antibody Response; Antigenic Diversity; Antigens; Autoimmune Process; B-Lymphocytes; Binding; Biological Warfare; Blood; Bone Marrow; Cavia; Cells; Central Africa; Cessation of life; Chiroptera; Complementarity Determining Regions; Complex; Democratic Republic of the Congo; Development; Disease; Disease Outbreaks; Ebola virus; Elements; Epitopes; Failure; Filovirus; Frankfurt-Marburg Syndrome Virus; Fruit; Gabon; Generations; Half-Life; Human; Immunization; Individual; Infection; Ivory Coast; Laboratories; Mediating; Mission; Molecular Immunology; Molecular Virology; Monoclonal Antibodies; Mus; Parainfluenza; Physiological; Population; Public Health; Publishing; RNA; Reagent; Recombinants; Research; Rodent; Rodent Model; Role; Route; Safety; Small Interfering RNA; Sudan; Surface; Survivors; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Therapeutic antibodies; Uganda; Vaccines; Vesicular stomatitis Indiana virus; Viral; Viral Hemorrhagic Fevers; Viral Pathogenesis; Virus; Virus Diseases; biosafety level 4 facility; bioterrorism/chemical warfare; biothreat; cross reactivity; env Gene Products; experience; human monoclonal antibodies; human subject; humanized monoclonal antibodies; immunogenic; member; molecular recognition; mortality; mouse development; neutralizing antibody; nonhuman primate; peripheral blood; polyclonal antibody; prevent; prophylactic; response; seropositive; success; weapons

The filoviruses Ebola (EBOV) and Marburg (MARV) cause the most severe hemorrhagic fevers in humans with the mortality rates up to 90% and are considered potential weapons for bioterrorism and biological warfare. Recently published studies demonstrated a successful protection of rodents and nonhuman primates (NHP) against filoviruses by passively transferred polyclonal antibodies (Abs) and mouse monoclonal antibodies (mAbs). However, fully human mAbs have important advantages over murine, chimeric, or humanized mAbs that include their safety and greater potency. The central hypothesis of this proposal is that survivors of EBOV and MARV Infections likely possess circulating B cells encoding naturally-occurring human Abs that neutralize virus and protect against disease. This hypothesis is supported by a recent progress of the research team included in the application in isolation of human mAbs from a survivor of MARV infection. The key requirements for successful treatment of filovirus infections with mAbs may include (A) use of high-affinity mAbs, and (B) administration of a "cocktail" of mAbs binding to the diverse viral epitopes, rather than an individual mAb. This possibility will be tested by generation of comprehensive reagents for study of filovirus recognition by human Abs which will be used for pursuing the following Specific Aims: 1) To isolate large panels of human mAbs to EBOV and MARV from the B cells of humans following natural infection; 2) To identify and characterize the most potent neutralizing and cross neutralizing human mAbs; 3) To test and optimize protection of human mAbs in rodents and NHP; 4) To test post-exposure treatment of NHPs with human mAbs in combination with recombinant VSV-vectored vaccines from RPI and anti-filovirus small interfering RNA (siRNA) from RP2. This proposal incorporates experts in molecular immunology, molecular virology, viral pathogenesis and public health, with access to BSL-4 facilities. We have access to blood of survivors of all five filovirus species highly pathogenic for humans {Zaire ebolavirus, Sudan ebolavirus, Bundibugyo ebolavirus, Ivory Coast ebolavirus, and MARV) in Gabon, Democratic Republic of Congo and Uganda, that is important due to the significant antigenic diversity between the individual species of filoviruses, and blood of individuals seropositive for EBOV infection who did not experience disease. The proposed research Is significant because it will result in generation of large panels of human mAbs that neutralize EBOV or MARV, identify the most potent mAbs and test them in rodents and NHPs on their own and in combination with the other post-exposure treatments included in the CETR.

埃博拉病毒（EBOV）和马尔堡病毒（MARV）引起人类最严重的出血热，死亡率高达90%，被认为是生物恐怖主义和生物战的潜在武器。最近发表的研究表明，通过被动转移的多克隆抗体 (Abs) 和小鼠单克隆抗体 (mAbs) 可以成功保护啮齿类动物和非人灵长类动物 (NHP) 免受丝状病毒的侵害。然而，全人单克隆抗体比鼠、嵌合或人源化单克隆抗体具有重要优势，包括安全性和更强的效力。该提议的核心假设是，EBOV 和 MARV 感染的幸存者可能拥有编码天然存在的人类抗体的循环 B 细胞，这些抗体可以中和病毒并预防疾病。这一假设得到了研究小组最近在从 MARV 感染幸存者中分离人类单克隆抗体的应用中取得的进展的支持。使用 mAb 成功治疗丝状病毒感染的关键要求可能包括 (A) 使用高亲和力 mAb，以及 (B) 施用与不同病毒表位结合的 mAb“混合物”，而不是单独的 mAb。这种可能性将通过生成用于研究人类抗体丝状病毒识别的综合试剂来测试，该试剂将用于实现以下具体目标： 1) 从自然感染后的人类 B 细胞中分离出大量针对 EBOV 和 MARV 的人类单克隆抗体； 2) 鉴定和表征最有效的中和和交叉中和人类单克隆抗体； 3) 测试并优化人单克隆抗体在啮齿动物和 NHP 中的保护作用； 4) 测试用人单克隆抗体与来自 RPI 的重组 VSV 载体疫苗和来自 RP2 的抗丝状病毒小干扰 RNA (siRNA) 组合对 NHP 进行暴露后处理。该提案汇集了分子免疫学、分子病毒学、病毒发病机制和公共卫生领域的专家，并可使用 BSL-4 设施。我们获得了加蓬、刚果民主共和国和乌干达对人类高致病性的所有五种丝状病毒（扎伊尔埃博拉病毒、苏丹埃博拉病毒、本迪布焦埃博拉病毒、科特迪瓦埃博拉病毒和 MARV）幸存者的血液，这一点很重要，因为丝状病毒的各个物种之间存在显着的抗原多样性，并且埃博拉病毒血清呈阳性的个体的血液 没有经历过疾病的感染者。拟议的研究意义重大，因为它将产生大量中和 EBOV 或 MARV 的人类单克隆抗体，识别最有效的单克隆抗体，并在啮齿动物和 NHP 中单独测试它们，并与 CETR 中包含的其他暴露后治疗相结合。