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

说明(申请人提供)：虽然抗菌剂对炭疽病感染的早期阶段有效，但延迟开始抗菌素治疗或感染抗药性菌株可能会导致危及生命的中毒状态，而抗菌剂对此无效。在这种情况下，需要中和毒素，因为抗菌剂会杀死营养细胞，对毒素没有影响。针对炭疽杆菌外毒素的多克隆抗体有可能立即中和毒素，提供一种挽救生命的医学对策，并填补一个重要的未得到满足的需求。动物研究已经证明，获得许可的疫苗BioThrax(R)或其主要蛋白质成分保护性抗原(PA)的抗体对预防和治疗吸入性炭疽病有效。此外，人类免疫球蛋白在治疗传染病，特别是细菌性毒血症方面有很长的安全和成功的历史。本文提出了静脉用炭疽免疫球蛋白(AIGIV)的新进展。AIGIV是从BioThrax免疫捐赠者的来源血浆中提取的，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验证的技术相比，使用经过验证的技术和许可的制造工艺为开发有效的、可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获得了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来源血浆数量。AIGIV高级开发计划允许在2006年12月之前发布cGMP AIGIV批次，这可能使AIGIV剂量在授予后18个月内根据紧急使用授权可供使用。该产品将用于治疗18-65岁人群中由抗生素敏感或耐药炭疽杆菌引起的吸入性炭疽病。对于接触过或接触过耐抗生素或对抗生素敏感的炭疽杆菌的风险人群(暴露前和暴露后的预防)，将寻求另一种预防吸入性炭疽的适应症。AIGIV高级开发的具体目标是：1)在兔和恒河猴模型中使用cGMP AIGIV进行药代动力学和耐受性研究，以及关键的动物法则疗效研究，以及2)开发和验证抗PA抗体和TNA检测方法，以支持生产和动物血清中AIGIV活性的测量。AIGIV最初的cGMP批次将用于动物规则研究，以确定提供预防和治疗保护作用的剂量，以防止炭疽杆菌气雾化孢子的攻击。

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.