Monoclonal Antibodies in Biodefense: Ebola Viruses

生物防御中的单克隆抗体：埃博拉病毒

• 批准号: 7476357
• 负责人: Larry Zeitlin
• 金额: $ 111.18万
• 依托单位: MAPP BIOPHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476357
• 关键词: Affect; Agglutination; Animal Testing; Animals; Antibodies; Antibody Specificity; Antigens; Biological Warfare; Cells; Complement-Dependent Cytotoxicity; Condition; Dose; Ebola virus; Epithelial; Epitopes; Evaluation; Farming environment; Guanosine Monophosphate; Half-Life; Human; Immunoglobulin Constant Region; Immunoglobulin G; Immunoglobulin Variable Region; Immunoglobulins; Immunotherapeutic agent; In Vitro; Infection; Kilogram; Lead; Macaca; Maize; Mammalian Cell; Military Personnel; Modeling; Monoclonal Antibodies; Mus; Parasitic Diseases; Passive Immunization; Phase; Plants; Process; Production; Prophylactic treatment; Range; Research Personnel; Role; Safety; Seeds; Serum; Survivors; System; Techniques; Technology; Transgenic Mice; Vaccines; Variant; Viral; Week; Zea mays; antibody-dependent cell cytotoxicity; base; biodefense; cost; day; human monoclonal antibodies; immunogenic; in vivo; milligram; novel; pathogen; prevent; programs; prophylactic; scaffold; scale up; toe corn; transcytosis; vector

DESCRIPTION (provided by applicant): Passive immunization with antibodies has been shown to prevent a wide variety of viral, bacterial, fungal, and parasitic diseases that affect humans. Indeed, effective antibody prophylactics are in military demand for protection against weaponized biowarfare agents and other human pathogens with biowarfare potential. This proposal provides the mechanism for establishing a process for the discovery and GMP manufacture of protective human monoclonal antibodies (Mabs). This process can readily be adapted to other biowarfare agents and used to respond to emerging and re-emerging pathogens. This proposal will focus on human Mab immunotherapeutics for the Ebola viruses (EBOVs). There are currently no vaccines or therapies for EBOVs. Mabs developed in the proposal can be produced under GMP conditions in plant for use as prophylactic countermeasures, providing immediate and sustained (human IgG serum half-life ~ 3 weeks) protection of military personnel or civilians, and may also have value in post-exposure prophylaxis and/or therapy. The first aim is to identify a panel of novel human Mabs against EBOVs using two complementary techniques. One isolates Mabs from seropositive survivors and the other generates a diverse panel of Mabs against epitopes that may not be immunogenic or immunodominant in natural human infection. In the second aim, the novel Mabs will be expressed in a rapid plant expression system as a variety of isotypes with constant regions from the different animal species for which EBOVs models are available. In the third aim, the role of antigen specificity, antibody isotype and antibody species of origin will be determined for prophylaxis and therapy using in vitro, murine, and macaque models of Ebola infection. In the final aim, the best Mab(s) will be selected for initiation of GMP production in corn. Since immunotherapeutics may need to be stockpiled in millions of doses, these products must be manufactured inexpensively and in large quantities. Plant production is dramatically cheaper than mammalian cell culture production and kilogram quantities of Mab can be produced per acre of corn. Production in plants can be inexpensively scaled-up to meet stockpile needs by simply planting seed on more farmed acres of land with current agronomic practices.

描述（由申请人提供）：抗体被动免疫已被证明可以预防影响人类的多种病毒、细菌、真菌和寄生虫疾病。事实上，军事上需要有效的抗体预防剂来防御武器化的生物战剂和其他具有生物战潜力的人类病原体。该提案提供了建立保护性人单克隆抗体 (Mab) 的发现和 GMP 生产流程的机制。该过程可以很容易地适应其他生物战剂，并用于应对新出现和重新出现的病原体。该提案将重点关注针对埃博拉病毒（EBOV）的人类单克隆抗体免疫疗法。目前还没有针对埃博拉病毒的疫苗或疗法。该提案中开发的单克隆抗体可以在工厂的 GMP 条件下生产，用作预防对策，为军事人员或平民提供即时和持续（人 IgG 血清半衰期~3 周）的保护，并且在暴露后也可能具有价值预防和/或治疗。第一个目标是使用两种互补技术鉴定一组针对 EBOV 的新型人类单克隆抗体。一种从血清阳性幸存者中分离出单克隆抗体，另一种则产生针对在自然人类感染中可能不具有免疫原性或免疫显性的表位的多种单克隆抗体。在第二个目标中，新型单克隆抗体将在快速植物表达系统中表达为具有来自不同动物物种的恒定区的多种同种型，这些动物物种具有 EBOV 模型。第三个目标是利用埃博拉感染的体外、小鼠和猕猴模型来确定抗原特异性、抗体同种型和抗体来源物种在预防和治疗中的作用。最终目标是选择最好的单克隆抗体用于启动玉米 GMP 生产。由于免疫治疗药物可能需要储存数百万剂量，因此这些产品必须廉价且大量生产。植物生产比哺乳动物细胞培养生产便宜得多，每英亩玉米可生产公斤量的单克隆抗体。只需在采用当前农艺实践的更多耕地上种植种子，即可以低成本扩大植物生产，以满足库存需求。