HUMAN ANTIBODIES FOR THERAPEUTIC INTERVENTION OF SEB EXPOSURE

用于 SEB 暴露治疗干预的人类抗体

• 批准号: 8173018
• 负责人: CHAD J. ROY
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173018
• 关键词: Aerosols; Amino Acids; Antibodies; Blood; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Dose; Drug Kinetics; Enterotoxins; Exposure to; Funding; Grant; Hour; Human; Human Development; Institution; Lethal Dose 50; Macaca mulatta; Plasma; Process; Reagent; Research; Research Personnel; Resources; Source; Staphylococcal Enterotoxin B; Testing; Therapeutic; Therapeutic Intervention; Therapeutic antibodies; Time; Toxin; United States National Institutes of Health; Western Blotting; in vivo; pre-clinical; therapeutic evaluation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This research plan relates to the preclinical development of antibodies capable of neutralizing staphylococcal enterotoxin B (SEB) in vivo. The ultimate objective of this proposal is the development of Human Anti-SEB MAbs (HASMs). Thus far, we have completed a full pharmacokinetics study with MORAb-048 (the candidate therapeutic antibody) in rhesus macaques. We have also performed a preliminary therapeutics evaluation against SEB toxin in rhesus macaques. The experimental therapeutic (MORAb-048) was administered either intravenously or intramuscularly and blood was drawn at 12 preselected time points. Results of the study show a rapid increase in plasma levels in IV-administered MORAb-048, whereas peak levels for IM administration are 48 hours postexposure. Using these data, we administered the therapeutic to rhesus macaques (n=14) either 48 hours (IM) or immediately before (-30 min) aerosol exposure to SEB toxin. Results of the aerosol exposure showed that, although the exposure concentration provided was congruent with a lethal dose (1 LD50), the challenge failed to effect the majority of the untreated controls (n=4, 3/4; 75% survival). Further analysis of the challenge material indicated that the loss of critical amino acid chains during the enterotoxin purification process limited the toxic potential of the reagent. As a result, the aerosol challenge with SEB was not adequate to test the protective capacity of the therapeutic under testing (MORAb-048). This study is being repeated with challenge material that has been assurance-purified using Western blot analysis to confirm the complete structural integrity of the SEB reagent.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该研究计划与能够中和体内中和葡萄球菌肠毒素B（SEB）的抗体的临床前开发有关。该提案的最终目标是人类抗seb mabs（HASMS）的发展。 到目前为止，我们已经完成了一项完整的药代动力学研究，其中包括恒河猕猴中的Morab-048（候选治疗抗体）。 我们还对猕猴中的SEB毒素进行了初步的治疗方法。 实验性治疗（MORAB-048）是静脉或肌肉内给予的，并在12个预选时间点以12个预选时间进行了血液。 该研究的结果表明，IV管理的MORAB-048的血浆水平迅速增加，而IM给药的峰值水平是暴露后48小时。 使用这些数据，我们对恒河猕猴（n = 14）进行治疗48小时（IM）或（-30分钟）气溶胶暴露于SEB毒素之前。 气溶胶暴露的结果表明，尽管提供的暴露浓度与致命的剂量（1 LD50）一致，但挑战未能影响大多数未经处理的对照（n = 4，3/4; 75％生存率）。 对挑战材料的进一步分析表明，肠毒素纯化过程中关键氨基酸链的损失限制了试剂的毒性潜力。 结果，SEB的气溶胶挑战不足以测试正在测试的治疗性的保护能力（Morab-048）。 这项研究正在用挑战材料重复，该挑战材料已通过Western印迹分析（确认SEB试剂的完整结构完整性）进行了保证纯化。