HUMAN ANTIBODIES FOR THERAPEUTIC INTERVENTION OF SEB EXPOSURE

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;本项目的最终目标是开发人抗SE B单克隆抗体（HASMs）。已经鉴定出至少两种HASM可以在体内阻断SEB活性。本项目的目的是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。在本工作计划中，一个目标是通过使用Morphotek的名为morphogenics的抗体优化技术增加其亲和力来进一步提高当前HASM的效力，并找到允许降低HASM剂量（例如1，000人LD 50）的HASM组合和比例。一个主要目的是证明用气溶胶SEB激发并用HASM治疗的恒河猴的存活率。 在TNPRC进行的一项非人灵长类动物研究将：1）确定HASM在非人灵长类动物体内的生物半衰期，并与确定在小鼠中有效的摩尔比相关，2）确定HASM在用雾化SEB激发的恒河猴非人灵长类动物中的疗效。 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.