Anthrax Immune Globulin to Prevent & Treat Anthrax: Advanced Product Development

炭疽免疫球蛋白预防

• 批准号: 7276725
• 负责人: Ajoy Chakrabarti
• 金额: $ 148.51万
• 依托单位: EMERGENT PRODUCT DEVELOPMENT GAITHERSBUR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7276725
• 关键词: Accounting; Advanced Development; Aerosols; Age-Years; Animal Model; Animals; Anthrax Vaccines; Anthrax disease; Anthrax immune globulin; Antibiotic Resistance; Antibiotics; Antibodies; Antigens; Antitoxins; Authorization documentation; Avidity; Award; Bacillus anthracis; Bacillus anthracis spore; Bacteria; Binding; Biological Assay; Biothrax; Breathing; Buffers; Cells; Centers for Disease Control and Prevention (U.S.); Class; Clinical; Clinical Research; Clinical Trials; Collection; Communicable Diseases; Contracts; Coupling; Cutaneous; Cyclic GMP; Defensins; Development; Dominant-Negative Mutation; Dose; Drug Kinetics; Effectiveness; Emergency Situation; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Exotoxins; Exposure to; Failure; Glycine; Grant; Human; Immune Sera; Immunoglobulin G; Immunoglobulins; Immunotherapy; Individual; Infection; Intravenous Immunoglobulins; Letters; Licensing; Licensure; Life; Macaca mulatta; Manufacturer Name; Measurement; Measures; Medical; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Multi-Drug Resistance; Numbers; Oryctolagus cuniculus; Parents; Patients; Persons; Pharmaceutical Preparations; Plasma; Play; Positioning Attribute; Preparation; Prevention; Process; Property; Prophylactic treatment; Proteins; Proteolytic Processing; Publishing; Receptor Cell; Recombinant Immune Globulin; Recording of previous events; Recovery; Reproduction spores; Research Design; Research Personnel; Risk; Role; Safety; Septic Toxemia; Serum; Sister; Source; Speed; Staging; Technology; Testing; Therapeutic; Time; Toxin; United States; United States Food and Drug Administration; Vaccines; Vaccinia; Validation; aerosolized; analog; animal data; anthrax lethal factor; anthrax toxin; antigen processing; antimicrobial; base; biodefense; design; dosage; edema factor; experience; human neutrophil peptide 1; human study; inhibitor/antagonist; killings; manufacturing process; member; mortality; neutrophil; polyclonal antibody; prevent; programs; prophylactic; receptor; small molecule; success

DESCRIPTION (provided by applicant): While antimicrobials are effective against the early stages of anthrax infection, delayed initiation of antimicrobial therapy or infection with an antibiotic resistant strain can produce a life-threatening toxemic state for which antimicrobials are not effective. In such cases, neutralization of the toxin is required because antimicrobials kill vegetative cells and have no effect on the toxin. Polyclonal antibodies to the B. anthracis exotoxin have the potential to immediately neutralize the toxin, providing a life-saving medical countermeasure and filling an important unmet need. The effectiveness of antibodies to the licensed vaccine BioThrax(r) or its major protein component, protective antigen (PA), to prevent and treat inhalational anthrax has been demonstrated in animal studies. In addition, human immune globulins have a long history of safety and success in treating infectious disease, and in particular, bacterial toxemia. Proposed herein is the advanced development of anthrax immune globulin for intravenous use (AIGIV). AIGIV is derived from Source Plasma from BioThrax-immunized donors and is produced using an FDA-approved immune globulin purification process. The use of a proven technology and a licensed manufacturing process provides a low- risk approach for the development of an effective, licensable antitoxin compared to other high-risk unproven technologies. EIS, through its sister company BioPort, has access to the only FDA-approved anthrax vaccine, and thus is in the unique position to generate the quantities of BioThrax Source Plasma necessary to produce AIGIV on a long-term basis. The AIGIV advanced development plan allows for release of a cGMP AIGIV lot by December 2006, which could make AIGIV doses available for use under Emergency Use Authorization within 18 months of award. The product would be indicated for treatment of inhalational anthrax due to antibiotic-susceptible or antibiotic-resistant B. anthracis in persons 18-65 years of age. An additional indication will be sought for the prophylaxis of inhalational anthrax for individuals at risk for having contact with, or who have contacted, either antibiotic-resistant or antibiotic-susceptible B. anthracis (pre-exposure and post-exposure prophylaxis). The Specific Aims for advanced development of AIGIV are to: 1) Conduct pharmacokinetic and tolerability studies, and pivotal Animal Rule efficacy studies in the rabbit and rhesus macaque models using cGMP AIGIV, and 2) Develop and validate anti-PA IgG and TNA assays to support manufacturing and for the measurement of AIGIV activity in animal sera. The initial cGMP lot of AIGIV will be used for Animal Rule studies to define the dose which provides prophylactic and therapeutic protection against aerosolized B. anthracis spore challenge.

描述（由申请人提供）：虽然抗菌药物对炭疽感染的早期阶段有效，但延迟开始抗菌治疗或感染抗生素耐药菌株可能会产生危及生命的毒血症状态，而抗菌药物对此无效。在这种情况下，需要中和毒素，因为抗菌剂会杀死营养细胞并且对毒素没有作用。炭疽芽孢杆菌外毒素的多克隆抗体有可能立即中和毒素，提供挽救生命的医疗对策并满足重要的未满足需求。动物研究已证明针对许可疫苗 BioThrax(r) 或其主要蛋白质成分保护性抗原 (PA) 的抗体可有效预防和治疗吸入性炭疽。此外，人类免疫球蛋白在治疗传染病，特别是细菌毒血症方面具有悠久的安全性和成功历史。本文提出了静脉用炭疽免疫球蛋白（AIGIV）的先进开发。 AIGIV 源自 BioThrax 免疫供体的源血浆，并使用 FDA 批准的免疫球蛋白纯化工艺生产。与其他高风险的未经证实的技术相比，使用经过验证的技术和获得许可的制造工艺为开发有效的、可获得许可的抗毒素提供了一种低风险的方法。 EIS 通过其姊妹公司 BioPort 可以获得 FDA 批准的唯一炭疽疫苗，因此处于独特的地位，可以产生长期生产 AIGIV 所需的 BioThrax 源血浆。 AIGIV 高级开发计划允许在 2006 年 12 月之前发布 cGMP AIGIV 批次，这可以使 AIGIV 剂量在授予后 18 个月内根据紧急使用授权可供使用。该产品适用于治疗 18-65 岁人群因抗生素敏感或抗生素耐药炭疽杆菌引起的吸入性炭疽。对于有接触抗生素耐药性或抗生素敏感性炭疽芽孢杆菌风险或曾经接触过的个体，将寻求预防吸入性炭疽的额外适应症（暴露前和暴露后预防）。 AIGIV 高级开发的具体目标是：1) 使用 cGMP AIGIV 在兔子和恒河猴模型中进行药代动力学和耐受性研究以及关键的动物规则功效研究，以及 2) 开发和验证抗 PA IgG 和 TNA 检测，以支持生产和测量动物血清中的 AIGIV 活性。 AIGIV 的初始 cGMP 批次将用于动物规则研究，以确定针对雾化炭疽芽孢杆菌孢子攻击提供预防和治疗保护的剂量。