Diverse mix of Human MoAbs to treat Anthrax exposure

人类单克隆抗体的多种组合可治疗炭疽病暴露

• 批准号: 6645094
• 负责人: PHILLIP R MORROW
• 金额: $ 10万
• 依托单位: AVANIR PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6645094
• 关键词: Bacillus anthracis; SCID mouse; anthrax; antiantibody; antibody formation; antigen antibody reaction; bacterial antigens; bacterial toxins; bioterrorism /chemical warfare; cell line; clinical research; enzyme linked immunosorbent assay; human tissue; immunologic substance development /preparation; leukocytes; monoclonal antibody; neutralizing antibody; polymerase chain reaction; surface plasmon resonance

DESCRIPTION (provided by the applicant): The long-term goal of this proposal (phase I and II) is the development of a human monoclonal antibody-based preparation for use in treating B. anthracis (anthrax) exposure or for use prophylactically. This preparation would most likely be composed of multiple, different monoclonal antibodies. Such a preparation would fill a significant void in the arsenal of reagents available to treat this biowarfare threat. Phase I specific aims are: 1) Evaluate the human antibody response of peripheral blood leukocytes from AVA vaccinated donors in the human lymphocyte engrafted SCID mouse (hu-PBL-SCID system). Immunogens will include a) recombinant Protective Antigen (PA), b) the active fragment of PA, c) Lethal Factor (LF), and (optionally) d) the Lethal Toxin formed from PA+LF. Antigen specific serum human antibodies will be detected by 'ELISA, and neutralizing antibody levels will be measured using the murine macrophage cell line RAW. 2) Evaluate Lethal Toxin treatment as an in vivo approach to select mice making neutralizing antibodies. 3) Generate, from selected animals, an initial series of human monoclonal antibodies specific for PA, and possibly LF. These will be characterized for neutralizing activity, and using BIACORE, affinity and epitope grouping. The main goal of the phase II proposal will be the configuration of at least one combination of human monoclonals which could be evaluated in vivo for the ability to protect and/or rescue from B. anthracis challenge. The phase II SBIR program may require the generation of a larger panel of antibodies, based on the success of phase I.

描述（由申请人提供）：该提案（第一阶段和第二阶段）的长期目标是开发基于人单克隆抗体的制剂，用于治疗炭疽杆菌（炭疽）暴露或预防性使用。该制剂很可能由多种不同的单克隆抗体组成。这种制剂将填补可用于治疗这种生物战威胁的试剂库中的重大空白。 第一阶段的具体目标是： 1) 评估人淋巴细胞移植 SCID 小鼠（hu-PBL-SCID 系统）中 AVA 疫苗接种供体的外周血白细胞的人抗体反应。免疫原将包括a)重组保护性抗原(PA)，b)PA的活性片段，c)致死因子(LF)，和(可选)d)由PA+LF形成的致死毒素。将通过“ELISA”检测抗原特异性血清人抗体，并使用鼠巨噬细胞系RAW测量中和抗体水平。 2) 评估致命毒素治疗作为选择小鼠产生中和抗体的体内方法。 3) 从选定的动物中产生一系列对 PA 和可能对 LF 具有特异性的人类单克隆抗体。这些将被表征为中和活性，并使用 BIACORE、亲和力和表位分组。 第二阶段提案的主要目标是配置至少一种人类单克隆抗体组合，可以在体内评估其保护和/或拯救免受炭疽芽孢杆菌攻击的能力。基于第一阶段的成功，第二阶段 SBIR 计划可能需要产生更大的抗体组。