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

炭疽免疫球蛋白预防

• 批准号: 7678466
• 负责人: Ajoy Chakrabarti
• 金额: $ 3.4万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678466
• 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.); Clinical; Clinical Research; Clinical Trials; Collection; Communicable Diseases; Contracts; Coupling; Cutaneous; Cyclic GMP; Defensins; Development; Development Plans; Dominant-Negative Mutation; Dose; Drug Kinetics; Effectiveness; Emergency Situation; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Exotoxins; Exposure to; FDA approved; Failure; Gamunex; Glycine; Grant; Human; Immune Sera; Immunoglobulin G; Immunoglobulins; Immunotherapy; Individual; Infection; Intravenous; Intravenous Immunoglobulins; Letters; Licensing; Licensure; Life; Macaca mulatta; Manufacturer Name; Measurement; Measures; Medical; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Multi-Drug Resistance; 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; Vaccines; Vaccinia; Validation; aerosolized; analog; animal data; animal efficacy; animal rule; anthrax lethal factor; anthrax toxin; antigen processing; antimicrobial; base; biodefense; clinical lot; design; dosage; edema factor; effective therapy; experience; high risk; human neutrophil peptide 1; inhibitor/antagonist; killings; manufacturing process; member; mortality; neutrophil; polyclonal antibody; prevent; product development; programs; prophylactic; receptor; resistant strain; 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）：虽然抗菌药物在炭疽感染的早期阶段有效，但抗菌治疗的延迟开始或抗抗生素耐药菌株的感染可以产生威胁生命的毒性状态，抗菌药物无效。在这种情况下，需要中和毒素是因为抗菌剂杀死了营养细胞，并且对毒素没有影响。炭疽芽孢杆菌外毒素的多克隆抗体有可能立即中和毒素，提供挽救生命的医学对策并满足重要的未满足需求。在动物研究中已经证明了对许可疫苗生物群（R）或其主要蛋白质成分保护和治疗吸入炭疽的抗体的有效性。此外，人免疫球蛋白在治疗传染病，尤其是细菌毒血症方面具有悠久的安全性和成功史。本文提出的是暂时使用的炭疽免疫球蛋白的高级发育（AIGIV）。 AIGIV是从生物座免疫供体的源血浆中得出的，并使用FDA批准的免疫球蛋白纯化过程产生。与其他高风险未经证实的技术相比，使用验证的技术和许可的制造过程为开发有效的，可有效的抗毒素的开发提供了一种低风险的方法。 EIS通过其姊妹公司Bioport，可以使用唯一的FDA批准的炭疽疫苗，因此具有独特的位置，可以生成长期生产AIGIV所需的Biothrax源等离子体。 AIGIV先进的开发计划允许在2006年12月之前发布CGMP AIGIV批次，这可以在颁奖后的18个月内使AIGIV剂量可在紧急使用授权下使用。由于抗生素敏感或抗生素抗生素的嗜血杆菌在18-65岁的人群中，该产品将用于治疗吸入炭疽。对于有接触或与之接触的人，抗生素耐药性或抗生素易感性易感性链球菌的风险，将寻求吸入性炭疽病的预防症状的额外迹象。 AIGIV高级开发的具体目的是：1）使用CGMP AIGIV进行药代动力学和耐受性研究，以及在兔子和恒河猴在兔子和恒河猴中使用CGMP AIGIV进行的关键动物规则效率研究，以及2）开发和验证抗PA IgG和TNA分析，以支持和测量AIGIV Animal Sera中的生产和测量。最初的CGMP AIGIV批次将用于动物规则研究，以定义提供预防性和治疗性保护剂的剂量，以防止炭疽芽孢杆菌孢子孢子的挑战。

项目成果

Effect of anthrax immune globulin on response to BioThrax (anthrax vaccine adsorbed) in New Zealand white rabbits.

炭疽免疫球蛋白对新西兰白兔 BioThrax（吸附炭疽疫苗）反应的影响。

• DOI: 10.1128/aac.00460-13
• 发表时间: 2013
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Malkevich,NinaV;Basu,Subhendu;RudgeJr,ThomasL;Clement,KristinH;Chakrabarti,AjoyC;Aimes,RonaldT;Nabors,GaryS;Skiadopoulos,MarioH;Ionin,Boris
• 通讯作者: Ionin,Boris