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的人类抗体作为免疫疗法来对抗人类的炭疽感染。单抗83K7C和单抗63LID是利用噬菌体展示技术确定的两个领先候选抗体，该技术可以保护体内的老鼠免受致命的炭疽毒素攻击。这两种抗体通过不同的机制中和。为了确定对吸入性炭疽感染的有效性，并可能对这些候选药物进行区分，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挑战研究。如果显示出保护作用，这些研究将被用于开始满足美国食品和药物管理局要求的两种生物防御疗法动物模型的要求，这些动物模型因伦理原因不能在人类身上进行第二阶段和第三阶段临床测试(21CFR 314.610和601.91)。该项目已被分解为五个具体目标。1)必须为正在考虑的试验生产和提纯足够的抗体，这将在Kemp BioTechnologies，Inc.(马里兰州弗雷德里克)进行。申请人将对材料进行分析，并准备和验证试验剂量。2)在兔身上的药代动力学试验将在查尔斯河实验室(CRL)(马萨诸塞州伍斯特)进行，以帮助为孢子挑战试验建立适当的剂量和给药途径。3)兔孢子挑战试验将在巴特尔医学研究和评估设施(MREF)(俄亥俄州杰斐逊)进行。4)如果在兔身上证明有效，将在CRL进行一种或两种抗体的猴子药代动力学试验。5)在猴子身上进行的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挑战研究，以便从这些试验获得的数据可以接受FDA提交。如果在猴子身上进行的孢子挑战试验成功，我们将继续在这笔赠款的范围之外进行更多的临床前和第一阶段人体试验。

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.