Formulation Development for an Intramuscular Administer*

描述（由申请人提供）：炭疽杆菌是炭疽的病原体，已被国防部确定为生物战的首要目标，并被疾病控制中心确定为a类制剂。据估计，在一个50万人口的城市逆风方向2公里的线路上释放50公斤炭疽孢子3天后，将发生12.5万人感染，导致9.5万人死亡。这种情况的经济影响估计为每10万人接触炭疽造成262亿美元的损失。一个未被满足的主要需求是暴露于雾化孢子后对炭疽的有效治疗。本文提出的研究将证明，与IM制剂一起施用安希姆将有效地治疗暴露后炭疽单独或与抗生素联合使用。长期目标。Elusys的长期目标是生产我们的候选药物Anthim的液体或冻干制剂，这是一种有效的产品，用于治疗炭疽感染，具有良好的保质期和方便的IM给药途径，用于生物战紧急情况。Elusys正在积极开发候选药物Anthim，这是一种针对炭疽毒素保护性抗原成分的超高亲和力单克隆抗体（MAb）。该抗体已在动物模型中进行了测试，显示出保护动物免于死亡的有效性。具体的目标。我们假设，这里提出的配方研究将使生产一种稳定、保质期长的炭疽治疗药物成为可能，并且可以通过IM给药快速给药。具体目标#1：生产抗体，以支持可比性测试，配方开发和体内动物试验。里程碑1：生产40克抗体。具体目标2：开发一种稳定的商业化配方。里程碑2：开发出稳定配方的安替姆生产工艺。具体目标#3：通过相关动物模型的体内动物试验显示功效。里程碑#3：重新配制的Anthim与参考标准的比较结果。研究与开发方法。目前正在开发和测试用于生产细胞系的主细胞库（MCB）。抗体将从该细胞系中产生，用于制剂研究。将进行配方研究，以开发一种稳定的配方，其中包含在配方前研究中确定的安眠草的最大浓度和用于小批量生产的功能性冻干循环。在配方开发之后，将进行可比性程序以及体内和体外研究，将新配方与先前的参考标准进行比较。

DESCRIPTION (provided by applicant): Bacillus anthracis, the pathogen for Anthrax, has been identified as a top priority biowarfare target by the Department of Defense, and as a Category A agent by Centers for Disease Control. It is estimated that three days after the release of 50 kgs of anthrax spores along a 2 km line upwind of a city of 500,000 population, 125,000 infections would occur, leading to 95,000 deaths. The economic impact of such a scenario is estimated to be $26.2 billion per 100,000 exposed to Anthrax. A major unmet need is effective therapy for treatment of anthrax after exposure to aerosolized spores. The studies proposed herein will demonstrate that administration of Anthim with an IM formulation will be effective in treatment of post-exposure anthrax alone or in conjunction with antibiotics. Long term objectives. Elusys's long-term objective is to produce a liquid or lyophilized formulation of our drug candidate Anthim that is an effective product for the treatment of Anthrax infection and has a favorable shelf life and convenient IM route of administration for biowarfare emergency situations. Elusys is actively developing the drug candidate Anthim, an ultra high affinity monoclonal antibody (MAb) to the protective antigen component of the anthrax toxin. This antibody has been tested in animal models and shown to be efficacious in protecting animal subjects from death. Specific Aims. We hypothesize that the formulation studies proposed here will enable the production of an Anthrax therapeutic that is stable, has a long shelf-life and can be given rapidly via IM administration. Specific Aim #1: Produce antibody to support comparability testing, formulation development and in vivo animal testing. Milestone #1: Production of 40 grams of antibody. Specific Aim #2: Develop a stable formulation of Anthim for commercialization. Milestone #2: Development of process for production of a stable formulation of Anthim. Specific Aim #3: Show efficacy through vivo animal testing using a relevant animal model. Milestone #3: Comparable results of reformulated Anthim in comparison with the reference standard. Research & Development Methods. A Master Cell Bank (MCB) for the production cell line is currently being developed and tested. Antibody will be produced from this cell line for formulation studies. Formulation studies will be conducted to develop a stable formulation, containing the maximum concentration of Anthim determined in the pre-formulation study and a functional lyophilization cycle for making small batches. Following formulation development, a comparability program and both vivo and in vitro studies will be conducted to compare the new formulation to a previous reference standard.