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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究计划涉及能够在体内中和葡萄球菌肠毒素B（SE B）的抗体的临床前开发。该提案的最终目标是开发人抗SEB单克隆抗体（HASMs）。 到目前为止，我们已经在恒河猴中完成了MORAb-048（候选治疗性抗体）的完整药代动力学研究。 我们还进行了初步的治疗评价SEB毒素在恒河猴。 静脉内或肌内施用实验治疗剂（M0 RAb-048），并在12个预选时间点抽取血液。 研究结果显示，IV施用的M0 RAb-048的血浆水平快速增加，而IM施用的峰值水平是暴露后48小时。 使用这些数据，我们在48小时（IM）或在气溶胶暴露于SEB毒素之前立即（约30分钟）向恒河猴（n=14）施用治疗剂。 气溶胶暴露的结果表明，尽管提供的暴露浓度与致死剂量（1 LD 50）一致，但攻毒未能影响大多数未处理对照组（n=4，3/4; 75%存活率）。 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丢失限制了试剂的潜在毒性。 因此，使用SEB的气溶胶激发不足以测试待测治疗剂（MORAB-048）的保护能力。 使用已使用蛋白质印迹分析确保纯化的挑战材料重复本研究，以确认SEB试剂的完整结构完整性。