HUMAN ANTIBODIES FOR THERAPEUTIC INTERVENTION OF SEB EXPOSURE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究涉及体内中和葡萄球菌肠毒素B(SEB)抗体的临床前研究，该项目的最终目标是研制人抗SEB单抗(HASM)。至少有两种HASM已经被确定可以在体内阻断SEB的活性。该项目的目标是所建议的治疗方法的合理性和合理性；动物模型的有效性；我们抗体的毒理学和安全性参数(S)；化学、制造和对照(CMC)部分；临床方案的设计。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。在这项工作计划中，一个目标是通过使用MorPhotek名为形态发生学的抗体优化技术增加现有HASM的亲和力来进一步提高其效力，并找到能够降低HASM剂量的HASM组合和比例(例如1,000人LD50)。一个主要的目标是证明用气雾剂SEB挑战和HASM治疗的恒河猴的存活率。TNPRC的一项非人类灵长类研究将1)确定HASM在非人类灵长类动物体内的生物半衰期，并与被确定为有效的小鼠的摩尔比相关；2)确定HASM对雾化SEB挑战的恒河猴非人类灵长类动物的治疗效果。这项研究将于2009年3月开始。

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 relates to the preclinical development of antibodies capable of neutralizing staphylococcal enterotoxin B (SEB) in vivo; the ultimate objective of this project is to development Human Anti-SEB MAbs (HASMs). At least two HASMs have been identified that can block SEB activity in vivo. The aims of this project are 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 reverse SEB toxicity. In this work plan, one objective is to further improve the potency of the current HASMs by increasing their affinities using Morphotek's antibody optimization technology named morphogenics, and to find HASMs combinations and ratios that would allow lowering the HASMs dose (e.g. 1,000 human LD50). One major objective is to demonstrate survival of rhesus monkeys challenged with aerosol SEB and treated with HASMs. A nonhuman primate study at the TNPRC will 1) determine the biological half life of HASMs in vivo in nonhuman primates and correlate to molar ratios determined to be efficacious in mice, and 2) determine the therapeutic efficacy of HASMs in rhesus nonhuman primates challenged with aerosolized SEB. This study will begin in March 2009.