Human Antibody Therapeutics Against Anthrax

描述（由申请人提供）：我们研究的长期目标是开发完全人类抗体作为人类炭疽感染的免疫治疗药物。Mab 83K7C和Mab 63LID是利用噬菌体展示技术鉴定的两种主要候选物，可保护大鼠体内免受致命炭疽毒素的攻击。这两种抗体通过不同的机制进行有效中和。为了确定对吸入性炭疽感染的疗效，并可能区分这些候选药物，以便将至少一种候选药物推向治疗用途，该应用程序专门针对兔和猴子的临床前药代动力学和孢子激发研究的表现。如果显示出保护作用，这些研究将用于开始满足FDA要求的生物防御疗法的两种动物模型的要求，这两种动物模型由于伦理原因不能在人类中进行II期和III期临床试验（21CFR 314.610和601.91）。这个项目被分成五个具体目标。1)必须为正在考虑的试验生产和纯化足够的抗体，这将在Kemp生物技术公司（Frederick， MD）进行。材料将由申请人进行分析，并准备和验证试验剂量。2)将在查尔斯河实验室（CRL）（马萨诸塞州伍斯特）进行兔药代动力学试验，以帮助确定孢子激射试验的适当剂量和给药途径。3)兔孢子挑战试验将在Battelle医学研究和评估机构（MREF） （Jefferson， OH）进行。4)如果在兔子身上证明有效，将在CRL进行一种或两种抗体的猴子药代动力学试验。5)猴孢子挑战试验将在巴特尔MREF进行。GLP条件将用于生产以及药代动力学和孢子激发研究，以便从这些试验中获得的数据可以接受FDA提交。如果在猴子身上的孢子挑战试验成功，我们将继续在本拨款范围之外进行额外的临床前和I期人体试验。

DESCRIPTION (provided by applicant): The long-term objective of our research is to develop fully human antibodies as immunotherapeutics against anthrax infection in humans. Mab 83K7C and Mab 63LID are two lead candidates identified using phage display technology that protect rats in vivo against a lethal anthrax toxin challenge. These two antibodies neutralize potently via differing mechanisms. In order to determine efficacy against an inhalational anthrax infection and possibly discriminate between these candidates so as to move at least one toward therapeutic use, this application is specifically targeted to the performance of preclinical pharmacokinetic and spore challenge studies in rabbits and monkeys. If protection is shown, these studies will be used to begin to fulfill the requirements for the two animal models requested by the FDA for biodefense therapeutics that cannot undergo Phase II and Phase III clinical testing in humans for ethical reasons (21CFR 314.610 and 601.91). The project has been broken down into five specific aims. 1) Sufficient antibody must be produced and purified for the trials under consideration, and this will be performed at Kemp Biotechnologies, Inc. (Frederick, MD). Material will be analyzed and trial dosages prepared and validated by applicant. 2) Pharmacokinetic trials in rabbits will be performed at Charles River Laboratories (CRL) (Worcester, MA) to help establish appropriate dosing and route of administration for spore challenge trials. 3) Rabbit spore challenge trials will be performed at Battelle Medical Research and Evaluation Facility (MREF) (Jefferson, OH). 4) If efficacy in rabbits is demonstrated, monkey pharmacokinetic trials with one or both antibodies will be performed at CRL. 5) Spore challenge trials in monkeys will be performed at Battelle MREF. GLP conditions will be used in production and for both the pharmacokinetic and spore challenge studies such that data obtained from these trials could be acceptable for FDA submittal. If spore challenge trials in monkeys are successful, we will continue with additional preclinical and Phase I human trials outside the scope of this grant.