Human Antibodies for Exposure/Protection from Anthrax

描述（由申请人提供）：Avanir Pharmaceuticals Inc.，已经开发了一个强大的平台，用于快速产生高亲和力的全人单克隆抗体，可以根据它们中和炭疽毒素PA的能力来选择所述抗体，如我们的主要候选物8 C1（Kd 1.2 × 10 - 12 M，KinExA）所例示的。在这里，我们建议继续发展8 C1以及分离和表征额外的全人单克隆抗体（MAbs）对B。炭疽外毒素主要由保护性抗原（PA）和致死因子（LF）组成。 我们将评估和表征单克隆抗体的亲和力（使用BiaCore和KinExA）和毒素中和（使用体外细胞测定法）。将在啮齿动物模型中使用重组炭疽毒素的推注攻击进一步评价选定的候选物。 通过使用多个人类供体，我们将获得一组不同的抗体，并确定体内中和炭疽外毒素所需的最佳候选抗体或抗体组合。在完成这项拟议的研究后，我们将有候选人准备进入下一阶段的动物模型评价。在暴露于气溶胶化炭疽孢子的活动物模型中测试候选物超出了本研究的范围/预算，将是第二阶段应用的合理切入点。 将执行以下具体目标： -1：产生一组对三联B的PA和LF组分的高亲和力全人抗体。炭疽外毒素 -2：在体外保护测定中评价和表征MAb结合和功效。 -3：使用重组炭疽毒素的推注攻击，确定啮齿动物模型中的保护功效。

DESCRIPTION (provided by applicant): Avanir Pharmaceuticals Inc., has developed a powerful platform for the rapid generation of high affinity fully human monoclonal antibodies that can be selected on their ability to neutralize anthrax toxin PA as exemplified by our lead candidate 8C1 (Kd 1.2 x10-12M, KinExA). Here we propose to continue the development of 8C1 as well as to isolate and characterize additional totally human monoclonal antibodies (MAbs) against B. anthracis exotoxin components protective antigen (PA) and lethal factor (LF). We will evaluate and characterize Mabs for affinity (using BiaCore and KinExA) and toxin neutralization (using an in vitro cell-based assay). Selected candidates will be further evaluated in a rodent animal model, using bolus challenge with recombinant anthrax toxins. By using multiple human donors, we will access a diverse a panel of antibodies and determine the optimal candidate(s) or combination of antibodies required to neutralize anthrax exotoxin in vivo. At the completion of this proposed study we will have candidates ready to enter the next stage of animal model evaluation. Testing candidates in live animal models with exposure to aerosolized anthrax spores are beyond the scope/budget of this study and would be the logical entry point for a phase II application. The following Specific Aims will be performed: -1: Generate a panel of high affinity fully human antibodies to PA and LF components of the tripartite B. anthracis exotoxin. -2: Evaluate and characterize MAbs binding and efficacy in an in vitro protection assay. -3: Determine protective efficacy in a rodent animal model, using bolus challenge with recombinant anthrax toxins.