Human antibodies for therapeutic intervention of staph enterotoxin B exposure

描述（由申请人提供）： 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。本提案的最终目标是准备在2010年前向FDA提交IND，用于人抗SEB单克隆抗体（HASMs）的临床开发。Morphotek和USAMRIID一直在合作研究和开发协议下进行合作，以进行创新研究，推动SEB以及其他生物战毒素的治疗方法的开发。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。该提案是对题为“生物防御毒素治疗和诊断合作研究伙伴关系”的申请（RFA）的回应，其中SEB是该RFA中包括的生物防御毒素之一。非常需要开发能够预防或逆转SEB毒性的疫苗和治疗策略，并且关于重要性，本申请列出了我们认为设计良好的结构化计划，以在3年内将我们的HASMs从当前的临床前阶段推进到临床开发。在该工作计划中，一个目标是通过使用Morphotek的名为形态发生学的抗体优化技术增加其亲和力来进一步改善当前HASM的效力，并找到允许降低HASM剂量（例如，在人中<7 mg/kg）或增加其中和能力（例如，阻断> 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激发并在4小时后用HASM处理的恒河猴的存活率。为了研究HASM的安全性，将在大鼠和食蟹猴中进行毒理学研究，并将根据GLP使用免疫组织化学评估HASM与正常人体组织的潜在交叉反应性。将优化HASM的生产工艺，以实现>0.5 g/L的滴度，并将生成GMP材料以支持毒理学研究。

DESCRIPTION (provided by applicant): 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 by the year 2010 for the clinical development of Human Anti-SEB MAbs (HASMs). Morphotek and USAMRIID have been collaborating under a Cooperative Research and Development Agreement to generate innovative research that will advance the development of therapeutics specific for SEB, as well as other biowarfare toxins. 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. This proposal is responding to a Request for Application (RFA) entitled "Cooperative Research Partnerships into Therapeutics and Diagnostics for Biodefense Toxins", whereby SEB is one of the biodefense toxins included in this RFA. There is considerable need to develop vaccines and therapeutic strategies capable of preventing or reverse SEB toxicity, and with regard to significance, this application lays out what we believe is a well designed, structured plan to advance our HASMs from their current preclinical stage to clinical development in 3 years. 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. <7 mg/kg in man) or increase their neutralization power (e.g. block >1,000 human LD50). One major objective is to demonstrate survival of rhesus monkeys challenged with aerosol SEB and treated 4 hours later with HASMs. To study the safety of HASMs, toxicology studies will be conducted in rats and cynomolgus, and potential HASMs crossreactivity to normal human tissues will be assessed using immunohistochemistry under GLP. The process for the manufacturing of HASMs will be optimized to achieve >0.5 gram/L titers and GMP material will be generated to support toxicology studies.