Human Antibody Therapeutics Against Anthrax

抗炭疽的人类抗体疗法

• 批准号: 6818227
• 负责人: Katherine S Bowdish
• 金额: $ 73.76万
• 依托单位: ALEXION PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818227
• 关键词: Bacillus anthracis; Macaca fascicularis; anthrax; antibacterial antibody; biotechnology; bioterrorism /chemical warfare; clinical research; cooperative study; dosage; drug administration routes; drug screening /evaluation; human subject; immunologic substance development /preparation; laboratory rabbit; military personnel; monoclonal antibody; phage display; pharmacokinetics

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.

描述（由申请人提供）：我们研究的长期目标是开发全人类抗体作为针对人类炭疽感染的免疫疗法。 Mab 83K7C 和 Mab 63LID 是使用噬菌体展示技术鉴定的两个主要候选药物，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有效中和。为了确定针对吸入性炭疽感染的功效，并可能区分这些候选物，以便将至少一种用于治疗用途，本申请专门针对兔子和猴子进行临床前药代动力学和孢子攻击研究。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对两种动物模型的要求，由于伦理原因，这些动物模型无法在人体中进行 II 期和 III 期临床测试（21CFR 314.610 和 601.91）。 该项目分为五个具体目标。 1) 必须为所考虑的试验生产和纯化足够的抗体，这将在 Kemp Biotechnologies, Inc.（弗雷德里克，马里兰州）进行。申请人将分析材料并准备和验证试验剂量。 2) 兔子体内的药代动力学试验将在 Charles River Laboratories (CRL)（马萨诸塞州伍斯特市）进行，以帮助确定孢子激发试验的适当剂量和给药途径。 3) 兔孢子激发试验将在巴特尔医学研究和评估机构 (MREF)（杰斐逊，俄亥俄州）进行。 4) 如果在兔子中证实疗效，将在 CRL 进行使用一种或两种抗体的猴药代动力学试验。 5) 猴子孢子挑战试验将在 Battelle 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。如果猴子的孢子挑战试验成功，我们将继续在本次拨款范围之外进行额外的临床前和第一阶段人体试验。