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

描述（由申请人提供）：虽然抗菌素对炭疽感染的早期阶段有效，但延迟开始抗菌素治疗或抗生素耐药菌株感染可能产生危及生命的中毒状态，此时抗菌素无效。在这种情况下，需要对毒素进行中和，因为抗菌剂会杀死营养细胞，对毒素没有作用。针对炭疽芽胞杆菌外毒素的多克隆抗体具有立即中和毒素的潜力，提供了挽救生命的医疗对策，填补了一个重要的未满足的需求。获得许可的疫苗biothrx (r)或其主要蛋白质成分保护性抗原（PA）的抗体在预防和治疗吸入性炭疽方面的有效性已在动物研究中得到证实。此外，人类免疫球蛋白在治疗感染性疾病，特别是细菌性毒血症方面具有悠久的安全性和成功的历史。本文提出了静脉注射用炭疽免疫球蛋白（AIGIV）的新进展。AIGIV来源于经biothrx免疫的供者的血浆，采用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许可的制造过程为开发有效的、可许可的抗毒素提供了低风险的方法。EIS通过其姊妹公司biopport，获得了唯一获得fda批准的炭疽疫苗，因此在生产长期生产AIGIV所需的biothrx源血浆方面处于独特的地位。AIGIV先进开发计划允许在2006年12月之前发布cGMP AIGIV批次，这可以在授予后的18个月内使AIGIV剂量在紧急使用授权下可用。本品适用于18-65岁人群因炭疽杆菌对抗生素敏感或耐药引起的吸入性炭疽的治疗。对于有接触或接触过抗生素耐药或抗生素敏感炭疽杆菌风险的个体，将寻求预防吸入性炭疽的附加指征（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疗效研究；2)开发和验证抗pa IgG和TNA检测，以支持生产和动物血清中AIGIV活性的测量。最初的cGMP批次AIGIV将用于动物试验，以确定对雾化炭疽芽孢杆菌攻击提供预防和治疗保护的剂量。

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.