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: 8358109
• 负责人: CHAD J. ROY
• 金额: $ 3.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358109
• 关键词: Address; Aerosols; Animal Model; Animals; Antibodies; Chemistry; Clinical; Clinical Protocols; Development; Dose; Dose-Limiting; Drug Kinetics; Enteral; Funding; Grant; Hour; Human; Human Development; In Vitro; Injection of therapeutic agent; Intoxication; Lethal Dose 50; Macaca mulatta; Modeling; National Center for Research Resources; Plasma; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Rodent Model; Safety; Source; Staphylococcal Enterotoxin B; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Toxicology; United States National Institutes of Health; base; cost; design; experience; humanized monoclonal antibodies; in vivo; nonhuman primate; particle; pre-clinical; prevent; therapeutic vaccine

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 to prepare for submission of an IND to the FDA for the clinical development of Human Anti-SEB MAbs (HASMs). Morphotek has identified at least two HASMs that can block SEB activity in vivo. The aims of this proposal address all the requirements for an IND submission including but not limited to: justification and rationale of the proposed therapeutic approach; efficacy in animal models; toxicology and safety parameters of our antibodies(s); chemistry, manufacturing and controls (CMC) section; design of clinical protocol. There is considerable need to develop vaccines and therapeutic strategies capable of preventing or reversing SEB toxicity. The humanized monoclonal antibody MORAb-048 has shown in vitro and in vivo (rodent models) to be specific to and neutralize SEB. This antibody was further evaluated in a nonhuman primate aerosol model of SEB intoxication. An initial pharmacokinetic profile of MORAb-048 indicated plasma levels peaked at approximately 48 hours after injection. Thereafter, MORAb-048 was administered prophylactically and animals were then exposed to either three or nine times the 50% lethal dose of purified SEB by small particle aerosol. Results indicated that MORAb-048 completely protected (100% survival) animals from SEB-induced lethality at the lower challenge dose (3x LD^50) and partially protected (83% survival) at the higher challenge dose (9x LD^50). Groups administered MORAb-048 appeared to experience a lower rate of clinical/enteric effects than unprotected animals. Collectively, these results show that MORAb-048 protects rhesus macaques from SEB-induced intoxication and there is a dose-limiting effect based upon an escalating challenge used in the study.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 该研究计划涉及能够在体内中和葡萄球菌肠毒素 B (SEB) 的抗体的临床前开发。该提案的最终目标是准备向 FDA 提交人类抗 SEB 单克隆抗体 (HASM) 临床开发的 IND。 Morphotek 已经鉴定出至少两种可以在体内阻断 SEB 活性的 HASM。该提案的目的是满足 IND 提交的所有要求，包括但不限于： 拟议治疗方法的理由和基本原理；动物模型中的功效；我们抗体的毒理学和安全参数；化学、制造和控制（CMC）部分；临床方案的设计。非常需要开发能够预防或逆转 SEB 毒性的疫苗和治疗策略。 人源化单克隆抗体 MORAb-048 在体外和体内（啮齿动物模型）中均显示出对 SEB 具有特异性并能中和 SEB。该抗体在 SEB 中毒的非人灵长类动物气溶胶模型中进行了进一步评估。 MORAb-048 的初始药代动力学特征表明血浆水平在注射后约 48 小时达到峰值。此后，预防性施用 MORAb-048，然后通过小颗粒气雾剂将动物暴露于 50% 致死剂量的三倍或九倍的纯化 SEB。结果表明，MORAb-048 在较低攻击剂量 (3x LD^50) 下完全保护（100% 存活）动物免受 SEB 诱导的致死，在较高攻击剂量（9x LD^50）下部分保护（83% 存活）。与未受保护的动物相比，给予 MORAb-048 的组似乎经历了较低的临床/肠道效应发生率。总的来说，这些结果表明 MORAb-048 可以保护恒河猴免受 SEB 诱导的中毒，并且根据研究中使用的逐步升级的挑战，存在剂量限制效应。