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）和马堡（Marv）（MARV）导致人类最严重的出血性发烧，死亡率高达90％，被认为是生物恐怖主义和生物战争的潜在武器。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），成功保护了啮齿动物和非人类灵长类动物（NHP）（NHP）对丝状病毒。但是，与鼠，嵌合或人性化的mAb相比，人体mAb具有重要的优势，包括其安全性和更大的效力。该提议的中心假设是，EBOV和MARV感染的幸存者可能具有编码自然疾病的人类ABS的循环B细胞，可以中和病毒并预防疾病。该假设得到了研究小组的最新进展，包括从MARV感染的幸存者隔离人MAB的应用中。成功治疗用mAB的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）给予与多种病毒表位的单元格的“鸡尾酒”，而不是单独的mAb。这种可能性将通过生成全面的试剂来研究人类ABS识别丝状病毒识别的试剂，该试剂将用于追求以下特定目的：1）将大量的人物mAB分离为EBOV和MARV与自然感染后人类B细胞的B细胞； 2）识别和表征最有效的中和和交叉中和的人mab； 3）测试和优化对啮齿动物和NHP中人物mAb的保护； 4）测试使用人物mAB的NHP与RP2的RPI和抗纤维病毒小型干扰RNA（siRNA）的重组VSV矢量疫苗结合使用。该提案结合了分子免疫学，分子病毒学，病毒发病机理和公共卫生的专家，并获得了BSL-4设施。我们可以接收人类的所有五种filevirus物种的鲜血（Zaire Ebolavirus，Sudan Ebolavirus，Sudan Ebolavirus，Bundibugyo Ebolavirus，Ivory Coast Ebolavirus和Marv）在Gabon，Gabon，Doppart of Doppart of Congos and uganda和乌干达共和国，这是由于欧洲民主共和国和乌干达的重要种类的鲜血，这是个人物种的重要性。没有疾病的感染。拟议的研究之所以重要，是因为它将导致大量的人物板中和，以中和EBOV或MARV，识别最有效的mAB，并自行在啮齿动物和NHP中对其进行测试，并与CERTER中包含的其他暴露后治疗结合使用。