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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 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。该提案的最终目的是准备向FDA提交人类抗SEB MABS（HASMS）的临床发展。 Morphotek已经确定了至少两个可以阻止体内SEB活性的HASM。该提案的目的涉及提交的所有要求的所有要求，包括但不限于：拟议治疗方法的理由和理由；动物模型的功效；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。需要开发能够预防或逆转SEB毒性的疫苗和治疗策略。 人源化的单克隆抗体MORAB-048已在体外和体内（啮齿动物模型）表现出特定于SEB并中和SEB的体内（啮齿动物模型）。在非人类灵长类动物的SEB中毒模型中进一步评估了该抗体。 MORAB-048的初始药代动力学特征表明血浆水平在注射后约48小时时达到峰值。此后，通过预防性施用MorAB-048，然后将动物暴露于小颗粒气溶胶纯化的SEB 50％或9倍。结果表明，MORAB-048在较低的挑战剂量（3x LD^50）下完全保护了SEB诱导的致死性（100％存活）动物，并在较高的挑战剂量（9x LD^50）处得到部分保护（83％存活）。与未受保护的动物相比，管理MORAB-048的组似乎经历了临床/肠影响的率较低。总的来说，这些结果表明，Morab-048可以保护恒河猕猴免受SEB诱导的中毒，并且基于研究中使用的不断提高的挑战具有限制剂量效果。