HUMAN ANTIBODIES FOR THERAPEUTIC INTERVENTION OF SEB EXPOSURE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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。本提案的最终目的是准备向FDA提交IND，用于人抗SEB单克隆抗体（HASM）的临床开发。Morphotek已经鉴定出至少两种HASM可以在体内阻断SEB活性。本提案的目的是解决IND提交的所有要求，包括但不限于：拟定治疗方法的依据和原理;动物模型中的疗效;我们抗体的毒理学和安全性参数;化学、生产和控制（CMC）部分;临床方案设计。有相当大的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M0 RAb-048已经在体外和体内（啮齿动物模型）显示出对SEB具有特异性并中和SEB。在SEB中毒的非人灵长类动物气溶胶模型中进一步评价该抗体。MORAb-048的初始药代动力学曲线表明血浆水平在注射后约48小时达到峰值。此后，将MORAb-048间接给药，然后通过小颗粒气溶胶将动物暴露于三倍或九倍于50%致死剂量的纯化SEB。结果表明，MORAb-048在较低的攻击剂量（3x LD ^50）下完全保护（100%存活）动物免受SEB诱导的致死性，在较高的攻击剂量（9 x LD ^50）下部分保护（83%存活）。与未受保护的动物相比，施用M0 RAb-048的组似乎经历较低的临床/肠效应率。总的来说，这些结果显示M0 RAb-048保护恒河猴免于SEB诱导的中毒，并且基于研究中使用的逐步增加的攻击，存在剂量限制作用。

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.